| Disorder | Clinical clues and diagnostic testing |
| Infectious etiologies | |
| Viral encephalitis (eg, HSV, HHV6, VZV, EBV, CMV, HIV, enterovirus, arbovirus) | CSF testing: Cultures, AFB smear, HSV1/2 PCR, HHV6 PCR, VZV PCR, EBV PCR, CMV PCR, HIV RNA, VDRL, Lyme antibodies, arbovirus panel, enterovirus PCR, T. whipplei PCR, 14-3-3, tau Serum testing: HIV, Lyme serologies Travel and exposure history |
| Bacterial encephalitis (eg, Listeria, Bartonella, Mycoplasma, Rickettsia) | |
| Spirochetal encephalitis (eg, syphilis, Lyme, leptospirosis) | |
| Fungal infection (eg, cryptococcus, coccidiomycosis, histoplasmosis) | |
| Tuberculosis | |
| Creutzfeldt-Jakob disease | |
| Whipple disease | |
| Toxic-metabolic | |
| Drug ingestion (eg, alcohol, ketamine, phencyclidine, organophosphates) | Serum and urine toxicology screens |
| Carbon monoxide | Carboxyhemoglobin, MRI (eg, diffusion restriction in basal ganglia, white matter) |
| Wernicke encephalopathy | Alcohol misuse or malnutrition, oculomotor dysfunction, MRI (periaqueductal gray, mamillary bodies, medial thalami) |
| Neuroleptic malignant syndrome | Causative medications (eg, neuroleptics, antiemetics, concomitant lithium), dopaminergic withdrawal, elevated creatine kinase |
| Vascular disorders | |
| Reversible posterior leukoencephalopathy syndrome | Headaches, hypertension, causative medications (eg, immunosuppression, angiogenesis inhibitors), MRI (posterior predominant or brainstem T2 hyperintensities) |
| Primary or secondary angiitis of the central nervous system | Abnormal vascular imaging, ANCA, cryoglobulins, aPL antibodies |
| Behçet disease | Painful mucocutaneous ulcers, uveitis, positive pathergy test |
| Susac syndrome (autoimmune vasculopathy) | Hearing loss, branch retinal artery occlusions on fluorescein angiography, MRI (corpus callosum and periventricular white matter abnormalities) |
| Neoplastic disorders | |
| Leptomeningeal metastases | MRI (leptomeningeal enhancement, communicating hydrocephalus), CSF cytology |
| Diffuse glioma | MRI (expansile, T2 hyperintense lesion), normal CSF |
| Primary or secondary central nervous system lymphoma | MRI (parenchymal or leptomeningeal enhancement); CSF cytology, flow cytometry, and IgH gene rearrangement |
| Demyelinating or inflammatory disorders | |
| Multiple sclerosis | CSF oligoclonal bands (nonspecific), lesions separated in time and space |
| Neuromyelitis optica | NMO antibodies |
| Acute disseminated encephalomyelitis (ADEM) | Preceding infection or vaccination; MRI with diffuse, multifocal, poorly demarcated lesions predominantly involving white matter; no new clinical or MRI findings after three months |
| Neurosarcoidosis | Hilar adenopathy or pulmonary parenchymal changes, elevated ACE level (nonspecific) |
| Neurodegenerative dementias | |
| Alzheimer disease dementia | MRI (often normal early in the course, may show focal atrophy); regional abnormalities on brain PET/SPECT, family history (for frontotemporal dementia) |
| Frontotemporal dementia | |
| Dementia with Lewy bodies | |
| Vascular cognitive impairment | |
| Psychiatric disease | |
| Schizophrenia and other psychotic disorders | Toxicology screens Family history Negative imaging and CSF |
| Bipolar disorder | |
| Conversion disorder | |
| Substance abuse | |
| Inherited and metabolic disorders | |
| Mitochondrial cytopathies | Serum or CSF lactate elevation, lactate peak on MR spectroscopy |
