Article Topic : Meningitis
Name of the Author : Hashem Mohammad Jameel Bani Ata
Keywords : meninges , meningismus , neuroinfectious disease

 

Overview

Meningitis is defined as inflammation of the meninges, diagnosed by an abnormal number of white blood cells in the cerebrospinal fluid and certain clinical signs and symptoms¹ . The cause could be chemical or infectious , however the most common causing micro-organisms are enteroviruses . Aseptic meningitis has self-limiting course , but bacterial one has high morbidity and mortality rates , so immediate treatement and diagnosis should be done². Patients with bacterial meningitis present with the abrupt onset of fever, headache and meningismus³ . Streptococcus pneumoniae and Neisseria meningitidis are the main bacterial caustive pathogens outside the neonatal age⁴ . classical clinical signs that are used to diagnose meningitis are nuchal rigidity, Kernig’s sign and Brudzinski’s sign⁵.

Epidemiology^{6 7}

Globally, bacterial meningitis has a prevalance rate of more than one million cases and 135,000 deaths annually. Continuous neurological complications occur in 9-25% of cases. However, administration of conjugate vaccines for Haemophilus influenzae type b, N. meningitidis, and S. pneumoniae contributes in decreasing the incidence of bacterial meningitis .

Etiology^{8 9 10}

The etiologies of meningitis ranges in severity of caused disease from benign and self-limited to life-threatening. Bacterial meningitis requires fast recognition and treatment. Aseptic meningitis is the most common form of meningitis especially viral and require supporutive treatment . enterovirus accounts for the most common cases of meningitis .

Viral meningitis :

• Enterovirus (most common cause)
• Herpes simplex virus
• Varicella zoster virus
• Arboviruses(e.g., West Nile virus)

Bacterial meningitis : depend on age, vaccination status, and recent trauma or instrumentation as illustrated in Table 1.

Table 1. Bacterial meningitis

Age /condition	Propaply pathogen
Infants within the first month	Streptococcus agalactiae, Listeria monocytogenes, Escherichia coli
Children 1 to 23 months of age	Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli
Age (2 -50 ) year	N. meningitidis, S. pneumoniae
Age > 50 / immunocompromiesd / alcoholics	S. pneumoniae, N. meningitidis, L. monocytogenes,
basilar skull fracture / cochlear implant	S. pneumoniae, H. influenzae
penetrating trauma / post neurosurgery	Staphylococcus aureus, aerobic gram-negative bacilli ( Pseudomonas aeruginosa), Coagulase-negative staphylococci
cerebrospinal fluid shunt	Staphylococcus aureus, aerobic gram-negative bacilli(Pseudomonas.aeruginosa), Propionibacterium acnes, Coagulase-negative staphylococci

 

Fungal menigitis 

Fungal systemic infection can reach the subarachnoid space and cause meningitis, either haematogeneously or due to trauma or surgery  . Major fungal pathogens are :

1. Neoformans,C. gattii, C. immitis : cause infection in immunocompetent and immunocompromised individuals . Cryptococcal meningitis is the most common fungal meningitis , and HIV is the largest risk factor for it . Other risk factors are steroid therapy, chronic disease in kidney, liver, or lung disease, malignancy and solid-organ transplants.
   Immunocompetent individuals with no chronic diseases commonly get infected by C. gattii causing Cryptococcal meningitis.
2. Histoplasma meningitis : causes infection in immunocompetent and immunocompromised individuals, particularly these patients are AIDS patients, solid-organ transplant recipients, receiving corticosteroids or TNF-α antagonists.
3. Coccidioides meningitis : Although immunosuppression state increases risk of Coccidioides meningitis , gentics play a major role in it , because Filipinos and African Americans have the highest incidence .
4. Candida meningitis : opportunistic fungi  that can disseminate through the CNS in immunocompromised state or a disrupted protective structures . It is most common in infants with an immature BBB, patients with ventriculoperitoneal shunts or ventriculostomies.

Parasitic(Eosinophilic) meningitis : presence of >10 eosinophils/μL in cerebrospinal fluid (CSF) . the most common causes are Angiostrongylus cantonensis and Gnathostoma spinigerum.

Noninfectious meningitis :

• Drug-induced (e.g., non-steroidal anti-inflammatory drugs, trimethoprim/sulfamethoxazole)
• Neurosarcoidosis
• Neoplastic meningitis
• Leptomeningeal carcinomatosis
• Benign recurrent lymphocytic meningitis (Mollaret meningitis)

The least common causes are :

• Behçet syndrome
• Central nervous system abscess
• Ehrlichiosis
• Human immunodeficiency virus
• Lyme disease (neuroborreliosis)
• Neurosyphilis
• Systemic lupus erythematous
• Tuberculous meningitis
• Vasculitis

Pathogenesis¹

There is no exact hypothesis  that explains the pathogenesis of meningitis. One hypothesis depends on Virchow-Robin space(VRS) as the following :
1.      Nasopharyngeal colonization.
2.      Penetration into the blood stream after crossing the mucosal membranes.
3.      Proliferation of micro-organisms in the bloodstream
4.      Extravasations across the endothelium of the post-capillary venules to the perivascular VRS.
5.      Passage from VRS to subpial space
6.      Moving through pia mater, infiltrating the CSF in the subarachnoid space
7.      Invasion of the meninges .

Clinical features^{12 13 8}

Presentation of meningitis has unique characterstics depending on the age group :

·         Neonate/ infant is non-specific in its clinical presentation as in older patients , so infant will look ill with one or more of the following: loss of appetite, irritability, vomiting, hypotonia, apnea , grunting, bulging fontanelle and seizure. Neck stiffness is uncommon.

 ·         Children: headache, fever, confusion, photophobia, nausea, vomiting, neck stiffness, irritability and seizure.

 ·         Adults present with at least two of these four symptoms ; headache, fever, neck stiffness and altered mental status. Patient may have petechial rash from either pneumococcal or meningococcal meningitis.

·         Patients older than 65 years of age may present with atypical presentation like non-specific confusion. Fever, headache and nuchal rigidity may not be present, moreover the Listeria monocytogenes is common in elderly patient.

Additionally, a good history is important to make a differential diagnosis¹⁷;  that includes :
·         Social history containing risk factors for sexually transmitted diseases.
·         Immune status and vaccination history of all patients.
·         Up to date medications are required because some medication groups (eg, IV immunoglobulin [IVIg], nonsteroidal anti-inflammatory medications) can lead to chronic meningitis.
·         Travel history, vocational history.
·         The presence of systemic symptoms or signs. including skin rash, joint pains, or mouth/genital ulcers, might sometimes provide diagnostic clues.

Complications¹⁴ may include seizures, Hydrocephalus, subdural collection, cerebral infarction, empyema, intracranial abscess, cranial nerve palsy , motor disability, intelligence quotient, sensorineural hearing loss, visual deficits and venous sinus thrombosis.

Figure 1 : hydrocephalus : Case courtesy of Radswiki, Radiopaedia.org.¹⁴

Physical Examination:

Classic physical examination maneuvers for the evaluation of meningitis that irritates the meningeal membrane are nuchal rigidity, Kernig’s sign and Brudzinski sign.

 Kernig’s sign is performed with the patient supine in position with hips and knees in flexion, the patient’s knee is extended. Pain involving the hamstring muscles as a result of stretching the inflamed sciatic nerve roots at angles less than 135°, indicates a positive Kernig’s sign .²⁰

 Brudzinski’s sign is performed while the patient is in a supine position. The examiner, one hand behind the patient’s head and the other on their chest, elevates the patient’s head while the other hand prevents the patient from rising. If the patient does have meningitis, passive flexion of the neck is going to pull the nerve roots through the meninges, both of which are inflamed, causing pain and involuntary movement of lower extremities. Therefore, flexion of the patient’s hips and knees after passive flexion of the neck indicates a positive Brudzinski sign .²⁰

Figure 2 : (a,b) : Kernig’s sign / (C) : Brudzinski’s sign ²¹

laboratory investigations  ^{18 19}

1. Blood culture

Blood samples should be drawn for culture , and are useful before starting the antibiotics , because antibiotics have an influence on the diagnosis . Blood cultures are positive in 50–80% of bacterial meningitis cases . To determine the exact pathogen, require microscopic investigation with gram stain and acid fast stain .

 2. Blood PCR  : Higher sensitivity rate compared to blood culture. It also has an important advantage being that it detects bacteria after antibacterial agent is administrated .

 

Lumbar puncture (LP)¹⁹

Lumbar puncture is the confirmatory test for meningitis. Cell count in CSF indicates if there’s inflammation or not , the type of leukocytes help in determining the cause of meningitis; Lymphocyte predominance suggests viral, whereas neutrophil predominance suggests bacterial infection also observed in tuberculous meningitis.

In addition , biochemistry of CSF is also helpful in diagnosis ; Cerebrospinal fluid glucose is normally approximately two-thirds the plasma concentration , but It is lower in bacterial and tuberculous meningitis , so we should consider the plasma  glucose when we approach lumbar puncture . Also , increased protein levels in CSF suggests inflammation . To determine the exact pathogen , require microscopic investigation with gram stain and acid fast stain. But one method with a higher sensitivity rate is CSF PCR , and its benefit is in patients who received antibiotics before LP .

TABLE 2. This table show parameters change with different pathogens.^{8 , 15}

Parameter	Normal	Bacterial	Viral	Tuberculous	Fungal
Opening presssure (cm CSF)	12–20	High	Normal or slightly raised	High	High
Appearance	Clear	Purulent	Clear	Clear /cloudy	Clear /cloudy
CSF WBC (cells/μL)	<5	>100	(5–1000)	(5–100)	(5–100)
Predominant cell		Neutrophils	Lymphocytes	Lymphocytes	Lymphocytes
CSF protein		High	Slightly raised	High	High
CSF Glucose level (mg/dL)	50 to 80	Usually <40	Mostly normal	low glucose level (< 40 mg/dL)	normal or low
CSF to blood  glucose ratio	>0.66	Very low	Normal or slightly low	Very low	low

 

Lumbar puncture contraindications:²² 

Contraindications were identified from many clinical research . The most important contraindications are:

1.       If the patient has low platelet levels >20,000/mm3 to 50,000/mm3 or elevated international normalized ratio (INR) can be at risk of subarachnoid hemorrhage.
2.       Presence of skin infection at the puncture site.
3.       Congenital spine abnormalities (e.g., tethered cord), LP procedure can be guided by fluoroscopy, ultrasound, or CT.
4.       Possible high intracranial pressure with brain herniation, in this case we should perform fundoscopy and CT/MRI Brain before LP. Significant clinical symptoms and signs for possible high intracranial pressure with brain herniation when a patient has focal neurological deficits, recent generalized seizures, abnormal level of consciousness, respiratory abnormalities, decorticate or decerebrate posturing, dilated or fixed pupil or papilledema at fundoscopy.

It’s also important to check medications before the procedure, like anticoagulant medications and if they can be temporarily discontinued or not.

Figure 3 : Papilledema secondary to meningitis.²³

Treatment^{8 18 22 24}

Patients with suspected acute bacterial meningitis need rapid diagnosis, empirical antimicrobial and early adjunctive therapy (high dose dexamethasone); strong inflammatory response has its negative sequelae hearing loss, deafness ,so adminstration of dexamethsone reduces the rate of occurance of these sequelae .

1.      Consider precaution droplet.
2.      Stabilization of the patient if they have breathing or circulatory difficulties.
3.      Intravenously dexamethasone with dose of 2 x 0.4 mg/kg/24h or 4 x 8-12mg/24h (0.15 mg/kg every 6 h for infants and children): High dose of dexamethasone is given to reduces the mortality and morbidity rate of acute bacterial meningitis. For maximum benefit, dexamethasone must be given early (first dose should be adminstrated either shortly before or simultaneously with antibiotics).
4.      Initiating empirical therapy; should begin therapy as soon as possible; delay may increase morbidity and mortality, such therapy should be initiated before CT brain if indicated. Recommended antibiotics are included in Table 3.
5.       Once the causative pathogen is determined, the empirical therapy is stopped and patient is started on the specific antimicrobial agent. (Table 4)

 Table 3. Recommended empirical antibiotics.

Age and condition	Recommended  therapy
Infant within 1st month	Ampicillin + cefotaxime
Age ( 2nd month – 50 year )	Vancomycin + ceftriaxone
Age > 50 year or immunocompromised or alcoholics patient	Vancomycin + ceftriaxone + ampicillin
basilar skull fracture / cochlear implant	Vancomycin / ceftriaxone
penetrating trauma / post neurosurgery / Patients with cerebrospinal fluid shunt	Vancomycin + cefepime

 Table 4. Pathogen specific therapy

Pathogen	Antibiotic	Duration of therapy (days)
Streptococcus pneumonia	Vancomycin + 3rd  generation cephalosporin	10 – 14
Neisseria meningitidis	3rd  generation cephalosporin	7
Listeria monocytogenes	ampicillin or penicillin	>= 21
Streptococcus agalactiae	ampicillin or penicillin	14 – 21
Haemophilus influenzae	3rd  generation cephalosporin	7
Escherichia coli	3rd  generation cephalosporin	21

 Viral meningitis requires supportive treatment only, acyclovir is not necessary unless the patient has impairment of consciousness, focal neurological signs and inflammation of temporal lobe in imaging Figure (4) ; because herpes encephalitis is suspected in this case, it should be treated with a high-dose of acyclovir for no fewer than 14 days and still will have about a 50% chance of permanent neurologic sequelae.

 Figure 4 : Herpes simplex encephalitis, Case courtesy of RMH Core Conditions, Radiopaedia.²⁵

Prevention²⁶

Meningococcal vaccination is recommended for these groups:
·         Infants aged 2 through 18 months.
·         Persons aged 9 months until 55 years of age.
·         Persons aged ≥56 years.

High risk situations that are recommended to get meningococcal vaccine:
·  Who suffer from Persistent Complement Component Deficiencies (C3, C5-9, Properdin, Factor D, and Factor H).
·  Anatomic or Functional Asplenia.
·  Human Immunodeficiency Virus.
·  Travelling to an epidemic country.

Table 5. Risk factors and the most common causative organism²⁷

Risk factor	Most common causative organism
Elderly > 65 years	S. pneumoniae, L. monocytogenes
Splenectomy / hyposplenic state	S. pneumoniae
Alcoholism	S. pneumoniae , L. monocytogenes
HIV/AIDS	S. pneumoniae, Salmonella spp
Diabetes mellitus	S. pneumoniae, L. monocytogenes
Cancer	S. pneumoniae, L. monocytogenes
Anatomical defect	S. pneumoniae
Organ transplant recipients	S. pneumonia, L. monocytogenes, Nocardia

 Prognosis:

Bacterial meningitis has a mortality rate of 14.8%.²⁸

The mortality for each pathogen:

·         S. pneumoniae is (16-37%). 

·         N. meningitidis is (5%). 

·         Haemophilus influenzae (3%). 

 And it is associated with bad outcomes as the following^{18 24} ;

·         Focal neurological deficits occurs in 50% of cases

·         Hearing impairment (14%); most common outcome.

·         Moderate to severe disability (14%) .

·         Cognitive impairments.

Viral meningitis is self- limiting, however in rare cases it is associated with long-term neuropsychiatric sequelae, particularly anxiety, depression  and neurocognitive dysfunction.²⁹

 

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