infections of the central nervous system - 台東馬...

INFECTIONS OF THE

CENTRAL NERVOUS

SYSTEM

Kuang-Nan Hsu

Neurological Department

Mackay Memorial Hospital, Taitung Branch

The brain and spinal cord are covered by 3 connective tissue layers

collectively called the meninges which form the blood-brain barrier.

What is meningitis?……

-the pia mater (closest to the CNS)

-the arachnoid mater

-the dura mater (farthest from the CNS).

The meninges contain cerebrospinal fluid

(CSF).

Meningitis is an inflammation of the

meninges, which, if severe, may become

encephalitis, an inflammation of the brain.

CNS infections

• Life-threatening problems with high associated

mortality and morbidity

• Meningitis - bacterial, viral and (rare) fungal

– acute, subacute, chronic

• Encephalitis - viral, bacterial, fungal

– acute, postinfectious (late), after vaccinations

– worldwide or endemic

– endogenous, exogenous, vector-borne

• Brain abscess - bacterial and (rare) fungal

– localization

• Other: meningoencephalitis, leukoencephalopathy

Meningitis

ACUTE CNS INFECTIONS

1. Bacterial meningitis***

2. Meningoencephalitis

3. Brain abscess

4. Subdural empyema

5. Epidural abscess

6. Septic venous sinus

thrombophlebitis

THE PATIENT WITH ACUTE CNS

INFECTION

Overall Goals in Management

1. To promptly recognize the patient with an acute

CNS infection syndrome

2. To rapidly initiate appropriate empiric therapy

3. To rapidly and specifically identify the etiologic

agent, adjusting therapies as indicated

4. To optimize management of complicating

features

Clinical manifestations

Meningitis

• headache, fever, neck

stiffness

• Brudzinski’s sign

• Kernig’s sign

• reduced consciousness

• Seizures (small children)

• cranial nerve palsies

• Vasculitis, focal signs

Symptoms and the Likelihood of

Meningitis

• Symptoms

– HA & fever

– HA, N/V

– HA, fever, N/V

– HA, fever, N/V,

photophobia

– HA, fever, N/V,

photophobia, stiff neck

• Odds of Meningitis

.42

.49

.56

.54

.57

Diagnostic Accuracy of Signs of

Meningeal Irritation in Pts with

Suspected Meningitis

Sign Sens Spec PPV NPV +LR -LR

Nuchal 30% 68% 26% 73% 0.94 1.02

rigidity

Kernig’s 5% 95% 27% 72% 0.97 1.0

Brudzinski’s 5% 95% 27% 72% 0.97 1.0

From:Thomas KE et al, CID 2002, 35:46-52

• 腦膜刺激症狀：

– 將病人頭部向前彎屈，則因疼痛而有阻力，呈現頸部僵硬的現象。這是因為腦膜受刺激，使頸椎及頸椎旁的肌肉發生痙攣所致。

– 當腦膜受到刺激時，將頸部用力抬高時，則可見到大腿在股關節處向前彎屈，稱為Bruzinski 氏徵(Bruzinski's sign)。

– 大腿彎屈後，將小腿拉直，會因腿後諸肌及後背的痙攣而有抗力，稱為 Kernig 氏徵(Kernig's sign)。

2015/5/27 Bacterial Meningitis13

– 據國外的報告，約有80%的腦膜炎病人有頸部僵硬、Bruzinski 氏徵或Kernig 氏徵等腦膜刺激症狀(Carpenter 1962)。國內的統計結果也差不多，腦膜炎病人中有76.1%發現有頸部僵硬現象 (劉,1978)。

– 但因細菌進入腦脊髓液後，約需數小時才會發生頸部僵硬現象。所以若病人沒有此現象時，也不能除去腦膜炎的可能性。

– 相反的，頸部僵硬的病人，也並不能說他一定有腦膜發炎，很多疾病也可引起頸部僵硬。例如小孩有急性咽喉炎、扁桃腺炎（尤其伴有扁桃腺周圍膿瘍時）、急性頸部淋巴腺炎時，可因頸部或肩胛部的肌肉痙攣而有頸部僵硬現象。


• 意識程度改變：

– 病人的意識程度依病情過程與嚴重程度而有所不同。早期常見有神智不清、譫妄等現象，到晚期可變成昏睡，木僵而進入昏迷。病情惡化或有昏迷現象時，前述的腦膜刺激現象可能會消失。

• 大腦的局部徵候(focal cerebral sign):

– 腦膜炎所產生的大腦局部徵候，常是暫時性的，如抽搐後的Todd‘s paralysis。若是發生持久的大腦局部徵候，可能是由於皮質部壞死、腦血管炎、腦梗塞或腦膿瘍所引起。


• 腦神經麻痺:

– 腦神經麻痺以暫時性的眼球轉動不良最為常見。這種腦神經麻痺，多是因壓迫或因滲出液直接侵犯到腦神經所引起。約有3%左右的腦膜炎病人會發生耳聾的後遺症。而聽力障礙的病人中，有37%是由腦膜炎所引起的(Smith 1988)。

• 視乳頭水腫:

– 腦膜炎本身極少發生視乳頭水腫。如有此現象必需考慮是否由腦膿瘍、硬腦膜下膿瘍或靜脈竇栓塞所引起。

• 皮膚症狀：– 腦膜炎雙球菌的病人中有66%在皮膚上可見到紫斑

(petechial) (Swartz 1965)。2015/5/27 Bacterial Meningitis16

• 抽搐 (convulsion):

– 腦部發炎所產生的神經症狀中，以抽搐最為常見，在兒科病童的發作率可高達30% ，尤其在由感冒嗜血桿菌所引致的腦膜炎病例中最多。抽搐可為局部或全身性發作，甚至形成持續性的發作。

• ###小孩的臨床症狀：– 三歲以下小孩的臨床症狀常不像成人那麼典型。在新生兒常只見其較激燥(irritable) 、拒食、嘔吐、經常哭鬧、腹部膨脹等非特異性的症狀而沒有腦膜刺激症狀。非但有時不發燒，在早產兒甚至有體溫下降的現象。因此只要小孩有敗血症的現象，不管是否有黃疸，便要懷疑有腦膜炎的可能。


APPROACH TO THE PATIENT WITH SUSPECTED

MENINGITIS

Decision-Making Within the First 30 Minutes

Clinical Assessment

Mode of presentation

Acute (< 24 hrs)

Subacute (< 7 days)

Chronic (> 4 wks)

Historical/physical exam clues

Clinical status of the patient

Integrity of host defenses

APPROACH TO THE PATIENT WITH

SUSPECTED MENINGITIS

Decision-Making at 1-2 Hours

CSF Analysis

CSF smears/stains

CSF antigen screens

CSF “profile”

CSF STUDIES

• Color/Clarity

• Cell counts/WBC diff

• Chemistries (protein, glucose)

• Stains/Smears (Gram)

• Cultures (routine)

• +/- Antigen screens

CSF SMEARS & STAINS

• GmS + in 60-90% of pts with

untreated bacterial meningitis

• With prior ATB Rx, positivity of GmS

decreases to 40-60%

• REMEMBER: + GmS = Heavy

organism burden & worse prognosis

CSF ANTIGEN SCREENS

• Bacterial antigen screens detect S.

pneumoniae, N. meningitidis, Hib, and GBS;

+ in 50-100% of pts (esp. useful in pts with

prior ATB Rx)

• Crypto antigen screen detects C.

neoformans; + in 90-95% of pts with crypto

meningitis

• Should NOT be a ordered routinely

CEREBROSPINAL FLUID PROFILES*

Neutrophilic/Low glucose (purulent)

Lymphocytic/Normal glucose

Lymphocytic/Low glucose

*Profile designation based on WBC

differentialand glucose concentration. After NE Hyslop,

Jrand MN Swartz, Postgrad Med 58:120, 1975.

BACTERIAL VS VIRAL MENINGITIS

Predictors of bacterial etiology:

• CSF glucose < 34

• CSF: Serum glucose ratio < 0.23

• CSF protein > 220

• CSF WBC count > 2000

• CSF neutrophil count > 1180

[Presence of any ONE of the above findings

predicts bacterial etiology with > 99%

certainty]

APPROACH TO THE PATIENT

WITH SUSPECTED MENINGITIS

Decision-Making at 24-48 hours

CSF Culture Results

Culture positive Adjust therapy based uponspecific organism and sensitivities

Culture negative Evaluate for “aseptic” meningitis syndrome

TO LP OR NOT TO LP

• Single most impt diagnostic test

• Mandatory, esp if bacterial

meningitis suspected

• If LP contraindicated, obtain BCs

(+ in 50-60%), then begin

empirical Rx

THE PATIENT WITH SUSPECTED

CNS INFECTION

Contraindications to LP

Absolute: Skin infection over site

Papilledema, focal neuro signs,

↓MS

Relative: Increased ICP without

papilledema

Suspicion of mass lesion

Spinal cord tumor

Spinal epidural abscess

Bleeding diathesis or ↓ plts

CNS INFECTIONS

CCT

• Over-employed diagnostic modality

Leads to unnecessary delays in Rx & added

cost

• Rarely indicated in pt with suspected acute

meningitis

• Mandatory in pt with possible focal

infection

• Increased sensitivity with contrast

enhancement

CCT Before LP in Patients with

Suspected Meningitis

• 301 pts with suspected meningitis; 235 (78%) had CCT prior to LP

• CCT abnormal in 56/235 (24%); 11 pts (5%) had evidence of mass effect

• Features associated with abnl CCT were age >60, immunocompromise, H/O CNS dz, H/O seizure w/in 7d, & selected neuro abnls

Hasbun, NEJM 2001;345:1727

CCT Before LP(Cont.)

• Neuro abnls included altered MS, inability to answer 2 consecutive questions or follow 2 consecutive commands, gaze palsy, abnl visual fields, facial palsy, arm or leg drift, & abnl language

• 96/235 pts (41%) who underwent CCT had none of features present at baseline

• CCT normal in 93 of these 96 pts (NPV 97%)

Hasbun, NEJM 2001;345:1727

CNS INFECTIONS

MRI

• Not generally useful in acute diagnosis

(Pt cooperation; logistics)

• Very helpful in investigating potential

complications developing later in

clinical course such as venous sinus

thrombosis or subdural empyema

THE PATIENT WITH SUSPECTED CNS

INFECTION

Role of Repetitive LP’s

1. Rarely indicated in proven bacterial meningitis unless

clinical response not optimal or as expected, fever

recurs, or infection is due to ATB resistant

pathogen

2. Essential in pts with “aseptic meningitis” syndromes to

monitor course &/or response to empiric therapies

3. Essential in pts with subacute/chronic meningitis of

proven etiology to assess response to Rx

4. Not routinely indicated at end-of-therapy for bacterial

meningitis

Bacterial Meningitis

• Pyogenic or bacterial infections of the

central nerve system

– Bacterial meningitis

– Septic thrombophlebitis

– Brain abscess

– Epidural abscess

– Subdural empyema

Pathogenesis and Pathology

• Acute inflammation reaction, mainly in the vascular pia

– Hyperemia

– Exudation of blood proteins and accumulation

– Migration of neutrophils

• Thrombosis of veins in the pia; brain infarction

• Meningeal exudate block the CSF; IICP; Tension hydrocephalus


• Subpial encephalopathy

• Ependymitis

• Inflammatoory or vascular involvement of

cranial nerve roots and spinal roots

• Meningeal fibrosis

• Chronic meningoencephalitis with

hydrocephalus


主要致病菌和年齡及用藥的關係


年齡主要致病菌首選抗生素

新生兒至一個月 B或D群鏈球菌、腸內菌

(第三代頭胞菌素 + Ampicillin)或 (Ampicillin + Aminoglycoside)

一個月至三個月感冒嗜血桿菌、肺炎雙球菌、腦膜炎雙球菌

(第三代頭胞菌素 + Ampicillin或氯黴素)

三個月至十八歲感冒嗜血桿菌、肺炎雙球菌、腦膜炎雙球菌


十八歲至五十歲感冒嗜血桿菌、肺炎雙球菌、李斯特菌


五十歲以上感冒嗜血桿菌、腸內菌，肺炎雙球菌、腦膜炎雙球菌、李斯特菌

(第三代頭胞菌素 + Ampicillin)或 (第三代頭胞菌素 + Penicillin G)

特殊考量

• 頭部開刀後：– 頭部開刀後發生腦膜炎的致病菌種，以革蘭氏陰性腸內桿菌最多(50%)，其次為Psuedomonas (10-15%)

、Staphylococcus aureus (10-15%)、 Staphylococcus

epidermidis(10%)及 Streptococci。

– 必需注意的是頭部開刀後的病人便會有頸部僵直、頭痛等腦膜炎的症狀，故只要發燒便需取得腦脊髓液做檢查。


• 腦脊髓液引流管 (CSF shunt)：– 15-25%的病人在放置腦脊髓液引流管期間會發生感染。

– 70% 以上在引流管剛放置的兩個月內發生。

– 最主要的菌種為 Staphylococcus epidermidis (佔50-

60%)、Staphylococcus aureus (佔25%)及革蘭氏陰性桿菌 (佔5-10%)。(Gardner 1988)


• 頭部外傷：– 頭部有骨折時，尤其是副鼻竇或耳朵附近所發生的骨折，可形成一使細菌能輕易侵入腦膜的通道。這種骨折常無法由Ｘ光檢查中發現，幾乎都是在病人屢次發生腦膜炎，或是有腦脊髓液的鼻漏或耳漏時才知道。

– 頭部外傷後併有腦脊髓液外滲時，並不一定會發生細菌性腦膜炎。腦膜炎可在外傷後數個月後，甚至數年後才發生。

– 若較晚發生腦膜炎時，致病菌種則以肺炎雙球菌佔 80% 最多(Keroack MA 1987) ，其它像Streptococcus、Neisseria、Haemophilus 及革蘭氏陰性桿菌則較少見。倘若外傷是由如子彈等外物所引起，因有異物、骨片、血塊或壞死組織存在，致病菌以金黃葡萄球菌為主。2015/5/27 Bacterial Meningitis41

• 頭部的感染病灶：– 頭部有感染病灶時，細菌可直接侵入腦膜，造成腦膜炎。

– 如有中耳炎時易發生肺炎雙球菌或感冒嗜血桿菌的腦膜炎。

– 腦膿瘍延伸至腦膜時，可由腦脊髓液培養出細菌。

– 頭顱或脊椎的骨髓炎，亦可直接侵入腦膜，造成腦膜炎。


• 其它疾病：

– 身體有其它疾病，造成免疫機能不全，以及接受抗癌或免疫抑制劑時，較容易受到某些細菌的感染。

– 例如鐮狀細胞貧血症(sickle cell anemia) 的病人易受肺炎雙球菌的感染。

– 脾臟切除後，也容易感染到肺炎雙球菌。

– 細胞免疫功能不全的病人，容易受到細胞內病原的侵犯，如Listeria、mycoplasma甚至 cryptococcus的感染。


特殊菌種的考量

• 1. 金黃色葡萄球菌(Staphylococcus aureus):

– 當在沒有頭部外傷或開刀病史的病人，培養出金黃色葡萄球菌時，病原菌是由菌血症(bacteremia) 來的，此時必須仔細檢查病人是否有心內膜炎(endocarditis)。

• 2. 厭氧菌 (anaerobes):

– 厭氧菌有可能是造成腦膜炎的致病菌，但不見。故當腦脊髓液培養出厭氧菌時，更有可能是同時併有腦膿瘍的病原菌，或是檢體污染的結果，必需小心做鑑別診斷。


• 3. Group A streptococci:

– 腦脊髓液培養出Group A streptococci 要注意病人是否有中耳炎 (otitis media)。

• 4. 多種細菌:

– 腦膜炎由多種細菌所造成時，意味著這個病人可能有中樞神經系統的腫瘤或是廔管(fistula) 存在。


Steroids?

• Value of dexamethasone for other than H. influenza

uncertain, but still recommended.

• For children over 2 months who have not been vaccinated

for Hib and for those with gram negative coccobacilli on

gram stain of CSF, give 0.15 mg/kg IV q 6hr x 4 days.

• Adults with a high concentration of bacteria in CSF(as

demonstrated with positive gram stain) and elevated ICP

should receive same regimen for 4 days.


Infection of the Brain Parenchyma

ABSCESSa focus of purulent infection

usually due to bacteria

•contiguous focus of

infection

•hematogenous

spread

Brain Abscesses

• Caused by hematogenous dissemination, trauma, contiguous spread from otitis, sinusitis or dental infection.

• Predominant organisms include Streptococcus milleri, Bacteroides, Staph aureus, proteus, and diphtheroids.

• Consider Aspergillus, Candida, Cryptococcus, Nocardia and Toxoplasma in immunocompromisedhosts

Abscess


•headache, focal signs, seizures

•no fever

•CSF is usually sterile

•bacteriologic diagnosis - by culturing an aspirate of the

abscess cavity

Treatment

•a poorly defined area of cerebritis - multiple antibiotics

•encapsulation - the abscess should be drained

Treatment of Brain Abscess

• Primary treatment with third generation cephalosporin + metronidazole. – Substitute vanc 2-4 gm IV/d for pen G if DRSP suspected

• Duration of treatment is unclear and determined by evidence of response on neuroimaging

• If CT scan suggests cerebritis, abscesses < 2.5 cm and Pt is neurologically stable and conscious, begin antibiotics and observe. Neurologic deterioration mandates surgical intervention.

• Subdural empyema is usually extension of otitis media or sinusitis. Rx same as brain abcess. Considered a surgical emergency with definitive treatment being bore hole/craniotomy drainage.

• Epidural abscesses occur after trauma or craniotomy or halo with osteo

• Treatment is surgical debridement followed by IV antibiotics (same as for brain abscess).

Spinal Epidural Abscess

• 50% result from blood borne infection from distant focus such as skin, pharynx, PID or endocarditis. May coexist with diskitis or osteomyelitis.

• Associated with IV drug use.

• Presents with fever, back pain and spinal tenderness. Cord symptoms follow with leg weakness, B/B dysfunction and sensory level.

• MRI imaging of choice with and without gad.

• Treated with surgical excision. Medical management reserved for poor surgical risks, lack of neurologic deficit, or Pt who have been paraplegic for >3 days.

Encephalitisinflammation of the brain

Etiology

mild forms of encephalitis

•enteroviruses, mumps, lymphocytic

choriomeningitis viruses

(arenaviruses, adenoviruses)

life-threatening viral encephalitis

•herpes simplex viruses and

arboviruses

uniformly fatal infection

•rabies virus

VIRAL MENINGITIS/ENCEPHALITIS

Enteroviruses

Polioviruses

Coxsackieviruses

Echoviruses

Togaviruses

Eastern equine

Western equine

Venezuelan equine

St. Louis

Powasson

California

West Nile

Herpesviruses

Herpes simplex

Varicella-zoster

Epstein Barr

Cytomegalovirus

Myxo/paramyxoviruses

Influenza/parainfluenzae

Mumps

Measles

Miscellaneous

Adenoviruses

LCM

Rabies

HIV

NONVIRAL CAUSES OF

ENCEPHALOMYELITIS

Rocky Mountain spotted fever Acanthamoeba

Typhus Toxoplasma

Mycoplasma Plasmodium

falciparum

Brucellosis Trypanosomiasis

Subacute bacterial endocarditis Whipple’s disease

Syphilis (meningovascular) Behcet’s disease

Relapsing fever Vasculitis

Lyme disease

Leptospirosis

Tuberculosis

Cryptococcus

Histoplasma

Naegleria

Clinical Presentation and treatment of

Encephalitis

• Classic presentation is headache, fever and altered

consciousness, usually prominent.

• Empiric treatment for HSV with acyclovir 10mg/kg q

8hours for 14 days.

• VZV may be treated with same regimen.

• CMV treated with either ganciclovir or foscarnet.

Encephalitis

Pathogenesis

Arboviruses (togaviruses, flaviviruses, and bunyaviruses)

•spread to the brain from the blood

•systemic infection causes few, if any, symptoms

•between 1 in 20 and 1 in 1000 infections are complicated

by CNS infection

•the encephalitis is diffuse, but is localized largely to

neurons

Encephalitis

Pathogenesis

Rabies

•acquired through the bite of a rabid animal

•axonal transport (from the inoculated skin or muscle to the

corresponding dorsal root ganglion or anterior horn cells and

then to populations of neurons throughout the CNS)

•typical behavioral changes of clinical rabies

Encephalitis


Herpes simplex virus-1

•focal temporal lobe signs

•headache, fever, hallucinations and bizarre behavior

•focal seizures, hemiparesis

•aphasia

Arbovirus infections

•a more diffuse and acute disease

•rapid depression of consciousness, greater frequency of

generalized seizures and multifocal signs

Encephalitis

•cultures for HSV - usually negative

•PCR

•EEG, computerized tomography

•brain biopsy

arbovirus infections

•IgM - in CSF

•inclusion bodies

•antigens or virus isolation

Encephalitis

Treatment

herpes simplex virus encephalitis

•acyclovir

other forms of viral encephalitis

•supportive care

arboviral encephalitis

•prevented by vaccines

•reduced by mosquito control

Chronic and Slow Infection of CNS

• TB Meningitis

• Fungus Meningitis

• Syphilis (Treponema pallidum); Lyme disease (Borrelia burgdorferi)

• Retroviruses (HIV, HTLV-1)

• Measles virus: subacute sclerosing panencephalitis (SSPE); JC

virus: progressive multifocal leukoencephalopathy; Rubella virus :

chronic encephalitis after congenital infection, relapse of a disease

in adolescence resembling SSPE

• Prions (spongiform encephalopathy agents) : kuru; Creutzfeldt-

Jakob disease, and nvCJD

infections of the central nervous system - 台東馬...

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