A 26-year-old man first developed behavioral symptoms at age 13 years. These symptom were characterized by inattention and personality change, and he was diagnosed with attention-deficit disorder. His academic performance progressively declined, with grades dropping from Bs in middle school to Cs and Ds in high school. By age 17 years, he developed a subtle gait and sphincter difficulties, although his progressive cognitive symptoms predominated. He graduated high school and attended community college with difficulty. Over the subsequent years, he became increasingly apathetic with reduced motivation. At the age of 25 years, he had his first brain MRI, which revealed global brain atrophy and numerous T2-weighted hyperintense and T1-weighted hypointense periventricular, subcortical, juxtacortical, brainstem, and spinal cord lesions (Figure, A-C). The lesions did not enhance with contrast. Diagnostic workup included complete blood count, comprehensive metabolic panel, Lyme serology, and testing for C-reactive protein level, thyroid function, antinuclear antibodies, vitamin B12 level, vitamin D level, human immunodeficiency virus, lipid profile, and homocysteine level; all of the results were normal. Cerebrospinal fluid studies showed a white blood cell count of 16/μL (to convert to ×109/L, multiply by 0.001), a red blood cell count of 0 × 106/μL (to convert to ×1012/L, multiply by 1.0), a glucose level of 61 mg/dL (to convert to millimoles per liter, multiply by 0.0555), a total cerebrospinal fluid protein level of 68.9 mg/dL, 20 oligoclonal bands, an IgG index of 1.07, and an IgG synthesis rate of 28.1 mg/dL. The results of the patient's cerebrospinal fluid VDRL test, Lyme polymerase chain reaction, and cytology were all negative. Neuropsychological testing demonstrated evidence of severe impairment in multiple modalities, including intellectual function, language, executive function, sensorimotor function, visual-spacial abilities, processing speed, attention and concentration, and memory. His performance was in the dementia range. He had relative preservation of academic performance (reading, comprehension, and math). He also met criteria for major depression and generalized anxiety. He was diagnosed with MS. Despite the absence of relapses, he was treated with several courses of steroids, glatiramer acetate, monthly intravenous immunoglobulin, and natalizumab without response. Neurological examination at age 26 years revealed a score of 20/36 on the Kokmen Mini-Mental Status Examination. Other pertinent positive results included the following: saccadic, smooth pursuits; a left extensor plantar response; and moderate difficulty on tandem gait. Given the prominent cortical atrophy and dominant cognitive presentation, a diagnostic right frontal brain biopsy was performed to exclude a superimposed primary neurodegenerative disorder.