Fever with headache and neck stiffness

Fever with headache and neck stiffness indicates meningeal inflammation until proved otherwise. Bacterial meningitis kills within hours and treatment must not wait for imaging or lumbar puncture.

Anatomy and mechanism. Pathogens reach the subarachnoid space by blood spread, direct extension (sinusitis, otitis, skull fracture) or neurosurgical contamination. Inflammation raises intracranial pressure, damages vessels and neurones, and causes hydrocephalus, infarction and seizures.

Classification by syndrome

• Acute bacterial meningitis (onset over hours to 1 to 2 days).
• Viral (aseptic) meningitis (onset over days, usually benign).
• Subacute or chronic meningitis (onset over 1 to 4 weeks or longer): tuberculous, cryptococcal, syphilitic, brucellar, fungal, neoplastic.
• Encephalitis (brain parenchymal inflammation with altered consciousness, seizures or focal signs), often with meningitis.
• Parameningeal focus: brain abscess, subdural empyema, spinal epidural abscess, septic cavernous sinus thrombosis.
• Noninfective mimics.

Epidemiology. Streptococcus pneumoniae is the commonest cause in adults and Neisseria meningitidis is the leading cause in young adults and during epidemics (the African meningitis belt, dry season). Listeria monocytogenes affects those over 50 years, pregnant women and immunocompromised patients. Cryptococcus is the commonest cause of meningitis in advanced HIV in many regions.

Clinical triad. Fever, neck stiffness and altered mental state occur together in fewer than half of adults with bacterial meningitis, though almost all have at least 2 of 4 features (headache, fever, neck stiffness, altered mental state).

Key distinctions. Sudden thunderclap headache points to subarachnoid haemorrhage. Cranial nerve palsies, a course over weeks and basal enhancement point to tuberculous or cryptococcal disease. Behaviour change, seizures and focal deficit point to encephalitis.

History

• Onset (hours or days), severity and character of headache, photophobia, vomiting, confusion, seizures, rash and neck pain.
• Preceding ear, sinus or throat infection, pneumonia, head injury, neurosurgery, lumbar puncture, spinal anaesthesia, cerebrospinal fluid leak, cochlear implant and dental work.
• Contacts with meningococcal disease, crowded living, boarding school or military recruits, and travel to the meningitis belt or Hajj.
• Vaccination history (meningococcal ACWY and B, pneumococcal, Haemophilus influenzae type b).
• HIV status, CD4 count, antiretroviral therapy, tuberculosis contacts, diabetes, alcohol use, asplenia, sickle cell disease, immunosuppression, cancer, and pregnancy.
• Animal contact, mosquito and tick exposure, unpasteurised dairy, bat exposure, sexual history (syphilis), and travel in the preceding 2 weeks.
• Drugs causing aseptic meningitis (NSAIDs, trimethoprim, intravenous immunoglobulin, azathioprine, carbamazepine).

Examination

• Vital signs, perfusion, Glasgow Coma Scale, and oxygen saturation.
• Neck stiffness (passive flexion), Kernig sign (pain on knee extension with the hip flexed) and Brudzinski sign (hip flexion on neck flexion). Sensitivity of these signs is low (under 30%) so absence does not exclude meningitis.
• Skin: petechiae, purpura, rash, herpetic lesions, and zoster.
• Neurological: focal deficit, cranial nerves (especially III, VI and VII), pupils, papilloedema, gait, and reflexes. Fundoscopy for papilloedema and malarial retinopathy.
• Ears, sinuses, mastoid, skull (fracture or discharge), spine (dermal sinus, tenderness) and genitalia (ulcer).
• Heart (murmur of endocarditis), lungs, abdomen (hepatosplenomegaly) and nodes.
• Signs of raised intracranial pressure: falling consciousness, bradycardia with hypertension, unequal or fixed pupils, abnormal posturing.

Red flags

• Reduced consciousness (Glasgow Coma Scale 12 or less), seizures, focal neurological signs, papilloedema or cranial nerve palsy.
• Nonblanching rash, hypotension, tachycardia or cold peripheries.
• Immunocompromise, advanced HIV (CD4 under 200 cells/microlitre), neutropenia, asplenia or sickle cell disease.
• Pregnancy, age over 50 years, and recent neurosurgery or head injury.
• Thunderclap onset.
• Fever with headache after travel to a malaria endemic area.
• Bradycardia with hypertension and irregular breathing (impending herniation).

Special groups

• Pregnancy: listeria cover with amoxicillin is added, and dexamethasone is still given. Doxycycline is avoided. Severe malaria and eclampsia are alternative causes of coma and seizures.
• Older adults: confusion without neck stiffness, with more listeria and Gram negative disease.
• Immunocompromised patients: absent fever or neck stiffness, with cryptococcus, tuberculosis, listeria, toxoplasmosis and syphilis.
• Kidney and liver impairment: adjust doses of aciclovir, vancomycin and antituberculous drugs.
• Children and neonates need age specific assessment and doses.
• Region specific: meningitis belt epidemics, cerebral malaria, tuberculous meningitis, cryptococcal meningitis, trypanosomiasis with late stage disease, rabies and neurocysticercosis.

Acute bacterial meningitis

• Pneumococcal meningitis.
• Meningococcal meningitis.
• Haemophilus influenzae meningitis.
• Listeria meningitis.
• Streptococcus suis meningitis (pork exposure).
• Gram negative meningitis (neurosurgery, immunosuppression, Salmonella in HIV).
• Staphylococcal meningitis (neurosurgery, endocarditis).
• Group B streptococcal meningitis (neonates, older adults).

Subacute and chronic meningitis

• Tuberculous meningitis.
• Cryptococcal meningitis.
• Neurosyphilis and syphilitic meningitis.
• Neurobrucellosis.
• Lyme neuroborreliosis.
• Histoplasma and coccidioides meningitis.
• Neoplastic (carcinomatous or lymphomatous) meningitis.
• Sarcoidosis, Behcet disease and other autoimmune meningitis.

Viral meningitis and encephalitis

• Enterovirus meningitis.
• Herpes simplex encephalitis and meningitis (type 2 recurrent).
• Varicella zoster meningoencephalitis.
• Mumps meningitis.
• Acute HIV meningitis.
• Arboviral encephalitis (West Nile, Japanese encephalitis, tick borne encephalitis).
• Rabies.
• Cytomegalovirus and Epstein-Barr virus encephalitis.
• Measles encephalitis and subacute sclerosing panencephalitis.
• Lymphocytic choriomeningitis.

Other infective

• Cerebral malaria.
• Rickettsial and leptospiral meningitis.
• East African and West African trypanosomiasis (late stage).
• Cerebral toxoplasmosis.
• Neurocysticercosis.
• Eosinophilic meningitis (Angiostrongylus).
• Amoebic meningoencephalitis.
• Brain abscess, subdural empyema and spinal epidural abscess.
• Septic cavernous sinus thrombosis and cerebral venous sinus thrombosis.
• Infective endocarditis with embolic meningitis.

Noninfective

• Subarachnoid haemorrhage.
• Drug induced aseptic meningitis.
• Autoimmune encephalitis (anti NMDA receptor and others).
• Systemic lupus erythematosus and vasculitis of the central nervous system.
• Hypertensive encephalopathy and posterior reversible encephalopathy syndrome.
• Pituitary apoplexy.
• Heat stroke, thyroid storm, neuroleptic malignant syndrome and serotonin syndrome.
• Migraine, cervical spine disease, and tension headache with a coincident fever.

Step 1. Do not delay antibiotics. Take blood cultures and glucose, then give antibiotics and dexamethasone within 1 hour of recognising possible bacterial meningitis. If lumbar puncture is not possible within 30 to 60 minutes, treat first.

Step 2. Decide whether imaging is needed before lumbar puncture. CT head first only when there is a focal neurological deficit, papilloedema, new seizure in the preceding week, immunocompromise, Glasgow Coma Scale of 12 or less, or suspected abscess or mass. Never delay treatment for CT.

Step 3. Contraindications to immediate lumbar puncture. Signs of raised intracranial pressure, haemodynamic instability, coagulopathy (platelets under 50 x 10^9/L or INR over 1.5), infection at the puncture site, and rapidly spreading purpura with shock.

Step 4. Blood tests

• Full blood count with differential, CRP, urea, creatinine, electrolytes, liver tests, glucose, lactate, coagulation screen and blood gas.
• Two sets of blood cultures before antibiotics (positive in about 50 to 80% of bacterial meningitis).
• Malaria rapid test and films, HIV test, syphilis serology, serum cryptococcal antigen, and pregnancy test.
• Meningococcal and pneumococcal PCR from blood when available.
• Procalcitonin or CRP has limited value in separating bacterial from viral disease.

Step 5. Cerebrospinal fluid. Measure opening pressure with the patient lying on the side with legs extended, and send at least 3 tubes for cell count with differential, protein, glucose (with a paired blood glucose), Gram stain, bacterial culture, PCR, and extra fluid for later tests. Add cryptococcal antigen and India ink in HIV or immunosuppression, and acid fast stain with nucleic acid amplification and mycobacterial culture (at least 6 mL of fluid) when tuberculosis is possible. Add VDRL and Treponema pallidum serology in neurosyphilis.

Interpretation. Bacterial meningitis can have fewer than 100 cells early. CSF lactate over 3.5 mmol/L supports bacterial disease. Partial antibiotic treatment lowers culture yield but PCR and cell counts remain abnormal for hours to days. Cryptococcal antigen lateral flow test is over 95% sensitive. Herpes simplex PCR can be negative in the first 72 hours, so repeat it after 3 to 7 days when suspicion persists and continue treatment meanwhile.

Step 6. Imaging. CT head with contrast or MRI brain for abscess, hydrocephalus, venous sinus thrombosis, infarction and encephalitis (temporal lobe changes in herpes). CT within 6 hours of onset for thunderclap headache, with lumbar puncture after 12 hours if CT is normal (looking for xanthochromia). Imaging of sinuses, mastoids and chest as indicated. Echocardiography when bacteraemia with Staphylococcus aureus or viridans streptococci is found.

Step 7. Additional tests. Electroencephalogram for encephalitis and nonconvulsive seizures. CD4 count. Autoimmune encephalitis antibodies in serum and CSF when infection is excluded.

Limits. Gram stain is positive in 60 to 90% of untreated bacterial meningitis (lower after antibiotics). Normal imaging does not exclude raised intracranial pressure. Tuberculous CSF nucleic acid amplification has sensitivity of about 70 to 90% with large volume samples, so a negative test does not exclude disease.

Immediate

• Airway, oxygen, intravenous access, blood cultures, glucose and lactate. Treat hypoglycaemia (glucose under 4 mmol/L) with dextrose 25 g intravenously.
• Resuscitate shock with crystalloid boluses of 250 to 500 mL with reassessment and noradrenaline to keep mean arterial pressure at 65 mmHg or over. Avoid hypotonic fluids and fluid overload in raised intracranial pressure.
• Ceftriaxone 2 g intravenously every 12 hours.
• Dexamethasone 10 mg intravenously every 6 hours for 4 days, with the first dose before or with the first antibiotic dose. Stop it if the final diagnosis is not bacterial meningitis. Evidence of benefit is limited in settings with high HIV prevalence and delayed presentation.
• Add amoxicillin 2 g intravenously every 4 hours for listeria cover when over 50 years, pregnant, or immunocompromised.
• Add vancomycin 15 to 20 mg/kg intravenously every 8 to 12 hours (loading dose 25 to 30 mg/kg in critical illness) when penicillin resistant pneumococcus is likely, after neurosurgery or with severe sepsis, directed by levels and kidney function.
• Penicillin allergy: meropenem 2 g intravenously every 8 hours when the reaction was not anaphylaxis. For anaphylaxis use chloramphenicol 1 g intravenously every 6 hours with vancomycin, and co-trimoxazole (5 mg/kg trimethoprim component intravenously every 6 to 8 hours) for listeria.
• Suspected encephalitis: aciclovir 10 mg/kg intravenously every 8 hours with hydration. Adjust for creatinine clearance 25 to 50 mL/min (every 12 hours), 10 to 25 mL/min (every 24 hours), under 10 mL/min (half dose every 24 hours). Start with the first antibiotic dose when confusion, seizures or focal signs are present.
• Isolate with droplet precautions for 24 hours after starting effective antibiotics when meningococcal disease is possible.
• Seizures: lorazepam 4 mg intravenously, repeated once after 10 minutes, then levetiracetam 60 mg/kg intravenously (maximum 4.5 g) over 10 minutes.
• Raised intracranial pressure: head up 30 degrees, sodium 140 to 150 mmol/L, avoid hypoxia and hypercapnia, and 3% saline 150 to 250 mL intravenously or mannitol 0.25 to 1 g/kg for herniation, with urgent neurosurgical and intensive care input.

Duration of definitive antibiotic therapy. Meningococcal 5 to 7 days. Pneumococcal 10 to 14 days. Haemophilus influenzae 7 to 10 days. Listeria 21 days (amoxicillin 2 g intravenously every 4 hours, with gentamicin 5 mg/kg intravenously once daily for the first 7 days). Gram negative and staphylococcal disease 21 days. Brain abscess: ceftriaxone 2 g every 12 hours plus metronidazole 500 mg intravenously every 8 hours for 6 to 8 weeks, with neurosurgical drainage for lesions over 2.5 cm.

Specific infections

• Meningococcal contacts: ciprofloxacin 500 mg orally once, or rifampicin 600 mg orally twice daily for 2 days, or ceftriaxone 250 mg intramuscularly once in pregnancy. Notify public health.
• Tuberculous meningitis: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 to 20 mg/kg orally daily for 2 months, then isoniazid and rifampicin for 10 months, with pyridoxine 25 to 50 mg daily. Give dexamethasone 0.4 mg/kg intravenously daily in the first week, reduced weekly over 6 to 8 weeks. Check liver tests every 2 weeks at first. Raised intracranial pressure and hydrocephalus need neurosurgical review. Start antiretroviral therapy in HIV after 2 to 8 weeks, in specialist care, because of paradoxical reactions.
• Cryptococcal meningitis: liposomal amphotericin B 3 to 4 mg/kg intravenously daily with flucytosine 25 mg/kg orally every 6 hours (reduce in kidney impairment) for 2 weeks, then fluconazole 400 to 800 mg orally daily for 8 weeks, then 200 mg daily until CD4 stays over 200 cells/microlitre for 6 months. A single dose regimen of liposomal amphotericin B 10 mg/kg with flucytosine and fluconazole 1200 mg daily is an option. Therapeutic lumbar puncture to drain 20 to 30 mL daily when opening pressure is over 25 cm CSF. Delay antiretroviral therapy for 4 to 6 weeks after starting antifungal treatment. Monitor potassium, magnesium and creatinine on amphotericin.
• Herpes simplex encephalitis: aciclovir 10 mg/kg intravenously every 8 hours for 21 days, with repeat lumbar puncture before stopping.
• Cerebral malaria: artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours then once daily, followed by a full course of oral artemether with lumefantrine. Monitor glucose every 4 to 6 hours.
• Neurosyphilis: benzylpenicillin 18 to 24 million units daily intravenously (3 to 4 million units every 4 hours) for 10 to 14 days.
• Viral meningitis: supportive treatment with paracetamol, fluids and antiemetics (ondansetron 4 to 8 mg orally or intravenously every 8 hours). Admit until bacterial meningitis is excluded.
• Subarachnoid haemorrhage: nimodipine 60 mg orally every 4 hours for 21 days, blood pressure control, and urgent neurosurgical referral.

Monitoring. Glasgow Coma Scale and neurological observations every 30 to 60 minutes initially. Fluid balance, sodium and glucose. Repeat blood count, creatinine, liver tests and CSF where response is poor. Check hearing before discharge in bacterial meningitis.

Referral and escalation. Intensive care for reduced consciousness, shock, status epilepticus and respiratory failure. Neurosurgery for hydrocephalus, abscess, subdural empyema and subarachnoid haemorrhage. Infectious diseases for tuberculous and fungal disease and immunocompromised patients. ENT for otogenic or sinus sources. Audiology and rehabilitation for survivors. Public health for meningococcal disease and outbreaks.

Admission criteria. All patients with suspected bacterial meningitis or encephalitis. Viral meningitis may be discharged only when bacterial disease is excluded and the patient is well, tolerating oral intake and able to return.

Discharge and follow up. Review hearing, cognition and neurological function at 4 to 6 weeks. Vaccinate against pneumococcus, meningococcus and Haemophilus influenzae type b where missed. Safety net advice: return for confusion, seizures, new weakness, vomiting, worsening headache, hearing change or fever after discharge.