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) |
Brain fog due to chemotherapy, polypharmacy, or post-COVID | History of exposure, temporal relation to the event |
Immune effector cell-associated neurotoxicity syndrome | Causative medication (eg, CAR-T cell therapy), concomitant cytokine release syndrome (often but not always) |
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 | Strokes involving multiple vessels, abnormal vascular imaging, ANCA, cryoglobulins, aPL antibodies, brain biopsy |
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 spectrum disorder | AQP4-IgG antibodies |
Myelin oligodendrocyte glycoprotein antibody-associated disease | MOG-IgG 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 |
Rasmussen encephalitis | Unilateral seizures and progressive neurologic deficits |
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 | |
Functional neurological symptom disorder (conversion disorder) | |
Substance abuse | |
Inherited and metabolic disorders | |
Mitochondrial cytopathies | Serum or CSF lactate elevation, lactate peak on MR spectroscopy |
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