Differentials
Viral meningitis
SIGNS / SYMPTOMS
Headache, neck stiffness, and fever with no altered mental status (maybe mild somnolence) or focal neurologic signs.
Frequently meningitis and encephalitis coexist (meningoencephalitis).
INVESTIGATIONS
MRI evidence of meningeal enhancement, with no evidence of brain parenchymal involvement.
Encephalopathy (toxic/metabolic)
SIGNS / SYMPTOMS
A multitude of metabolic factors and remote infections can cause brain parenchymal dysfunction without structural damage to the brain.
Frequently encountered in hospital/nursing home settings.
Altered mental status and even focal neurologic signs (hypoglycemia) can be seen with both conditions, and there are no specific clinical differentiating features.
INVESTIGATIONS
Normal cerebrospinal fluid analysis, normal MRI, electroencephalogram - diffuse slowing, triphasic waves.
Status epilepticus
SIGNS / SYMPTOMS
There are no specific clinical differentiating features, and status epilepticus is not uncommonly seen in patients with encephalitis so can be considered a clinical feature of this disease.
In cases that are clearly not due to encephalitis (MRI, cerebrospinal fluid negative), the patient frequently has a known seizure disorder with subtherapeutic levels of medications.
INVESTIGATIONS
Electroencephalogram - evidence of ongoing seizure activity.
Central nervous system vasculitis
SIGNS / SYMPTOMS
There are no specific clinical differentiating features. Headaches and focal neurologic signs can be seen.
INVESTIGATIONS
Differentiated by MRI, angiography, and biopsy.
MRI - evidence of multiple small strokes, usually cortical.
Angiography - can be normal but frequently a typical angiographic appearance of multisegment narrowing/beading of the vessels is noted.
Definitive diagnosis sometimes requires brain and meningeal biopsy, which will show evidence of inflammation (i.e., presence of inflammatory cells such as lymphocytes in the vessel wall and surrounding the blood vessel, along with structural alterations of the involved vessels).
Headache with neurologic deficits and CSF lymphocytosis (confusional migraine with pleocytosis)
SIGNS / SYMPTOMS
Acute confusion, psychosis, and focal neurologic deficits in association with migraine headache is seen in some migraine patients,[78] and in familial hemiplegic migraine.[79] These are suggestive of but not specific to migraine.
INVESTIGATIONS
Cerebrospinal fluid - elevated WBC count with no evidence of infection.
Malignant hypertension
SIGNS / SYMPTOMS
High blood pressure, headaches, altered mental status, and visual symptoms can be seen.
INVESTIGATIONS
Elevated BP (usually >220/110 mmHg). But may be sudden acute elevations even at lower blood pressure.
Differentiated by fundoscopy, CT, and MRI.
Fundus examination - papilledema and hemorrhage.
CT usually normal, but occasionally hypodense lesions seen over occipital lobes.
MRI: T2 and fluid attenuated inversion recovery (FLAIR) hyperintense lesions over the occipital lobes (usually asymmetric). Increased diffusion on diffusion-weighted imaging (with apparent diffusion coefficient maps showing increased diffusion) is also seen. The term "posterior reversible leukoencephalopathy syndrome (PRES)" is also used to describe the MRI changes.
Posterior reversible leukoencephalopathy syndrome (PRES)
SIGNS / SYMPTOMS
Headache, confusion, seizures, visual loss, focal deficits; pathogenesis includes immunosuppressive therapy, renal failure, eclampsia, hypertension, lupus.
INVESTIGATIONS
MRI: T2/fluid attenuated inversion recovery (FLAIR) lesions throughout the brain.
Intracranial tumors and cysts
SIGNS / SYMPTOMS
There are no specific clinical differentiating features.
A variety of clinical presentations, such as headache worse on awakening, altered mental status, seizures, and focal neurologic deficits are seen with intracranial neoplasms.
INVESTIGATIONS
CT and MRI imaging of the brain (preferably MRI) can help diagnose these conditions. Biopsy - required in some cases to make a definitive diagnosis.
Neurosarcoidosis
SIGNS / SYMPTOMS
There are no specific clinical differentiating features. Cranial neuropathies (especially CN II and VII), spinal cord involvement, disruption of the hypothalamic/pituitary axis, and peripheral neuropathy may be accompanying features. Additional systemic features include lung disease, erythema nodosum, lymphadenopathy, arthralgias, and uveitis.
INVESTIGATIONS
Brain MRI with contrast may demonstrate meningeal enhancement. LP may show pleocytosis (lymphocytic predominant) and elevated total protein; glucose levels are sometimes low. Serum and cerebrospinal fluid ACE levels can be assessed, but may yield both false negative and false positive results. Chest radiography, whole-body (18F)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and gallium scanning can be considered in individuals without a known diagnosis of sarcoidosis. Biopsy should be considered for pathologic diagnosis of noncaseating granulomas, especially if a non-CNS lesion is identified.
Systemic lupus erythematosus (SLE)
SIGNS / SYMPTOMS
There are no specific clinical differentiating features. Headache, neuropsychiatric issues, and seizures can be seen.
Systemic features include skin changes (e.g., butterfly rash, discoid rash), arthritis, serositis, hematologic abnormalities, renal disorder, and immunologic abnormalities.
INVESTIGATIONS
Serum immunology tests for antinuclear antibody, anti-double stranded DNA antibody, anti-Smith antibody, and antiphospholipid antibody are positive in most patients with SLE.
Intracranial bleed
SIGNS / SYMPTOMS
There are no specific clinical differentiating features. Headache, altered mental status, seizures, and focal neurologic deficits can be seen.
INVESTIGATIONS
CT and MRI can clearly demonstrate acute intracranial bleeds. In subarachnoid hemorrhage, a lumbar puncture may show xanthochromia and no change in the number of red blood cells from tube 1 to tube 4.
Traumatic brain injury
SIGNS / SYMPTOMS
A history of head injury is frequently obtained, but can be unavailable in someone who is found unresponsive.
Headache, varying degrees of altered mental status, and focal neurologic findings can be seen.
There are no specific clinical differentiating features.
INVESTIGATIONS
CT and MRI will reveal various intracranial bleeds that are associated with head injury; concussions have normal imaging findings; diffuse axonal damage can be seen as signal abnormality in MRI images.
Ischemic stroke
SIGNS / SYMPTOMS
There are no specific clinical differentiating features.
Sudden onset of focal neurologic deficits, altered mental status, seizures, and headaches.
Certain strokes, such as those involving the posterior cerebral artery, basilar artery, and anterior cerebral artery, can present with an encephalopathic clinical picture.
It is important to note that ischemic stroke can also occur as a complication of some cases of encephalitis.
INVESTIGATIONS
CT scan - low attenuation in the involved areas.
MRI - diffusion-weighted imaging evidence of decreased diffusion is characteristic of acute ischemic stroke. Fluid attenuated inversion recovery (FLAIR) and T2 hyperintense lesions are seen in subacute cases.
Mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS)
SIGNS / SYMPTOMS
There are no specific clinical differentiating features. Hearing loss, encephalopathy, seizures, stroke-like episodes, and presence of lactic acidosis are characteristic clinical features.
INVESTIGATIONS
Cerebrospinal fluid lactate - elevated
MRI - T2 hyperintense signal in territory not conforming to major vascular regions. Diffusion-weighted imaging evidence of increased diffusion.
Genetic test - mitochondrial DNA point mutations (A3243G mutation in 80% of cases).
Muscle biopsy - ragged red fibers on modified Gomori trichrome stain.
Inborn errors of metabolism
SIGNS / SYMPTOMS
History of parental consanguinity, early neonatal death, maternal acute fatty liver of pregnancy and HELLP syndrome (elevated liver enzymes and low platelets) in pregnancy. May be lethargic and irritable with poor feeding. Physical exam may reveal jaundice, cataracts, hepatosplenomegaly, abnormal muscle tone, dysmorphism (e.g., coarse facial features), and abnormal body odor. May present with life-threatening encephalopathy.[80][81]
INVESTIGATIONS
Serum ammonia may be elevated (urea cycle defect, organic acidemias). Arterial blood gas can show a metabolic acidosis with elevated anion gap. Urine orotic acid is low in carbamyl phosphate synthetase deficiency and elevated in ornithine transcarbamylase deficiency.[81]
Bacterial meningitis
SIGNS / SYMPTOMS
History of headache, neck stiffness, photophobia, and fever.
Physical exam may reveal fever, neck stiffness, and focal neurologic abnormalities.
INVESTIGATIONS
Cerebrospinal fluid shows elevated WBC often with neutrophil predominance, elevated protein, and low glucose. Gram stain and polymerase chain reaction may reveal the causative organism.[82]
Fungal meningitis
SIGNS / SYMPTOMS
History of headache, neck stiffness, photophobia, and fever.
History of immunosuppression may be present.
Physical exam may reveal fever, neck stiffness, and focal neurologic abnormalities.
INVESTIGATIONS
Cerebrospinal fluid culture may demonstrate fungal growth.
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