NeuroQuiz Section Editor: Lawrence S. Honig, MD, PhD, Columbia University, New York, New York.
A 60-year-old woman presented with a 10-year history of gradually deteriorating cognitive and then motor dysfunction. The first symptoms were subtle increasing memory and word-finding difficulty, and then she developed mild dysarthria. By the fourth year, she developed fatigue, hand clumsiness, gait disorder, and urinary incontinence, and a multilevel cervical laminectomy was performed. Bilateral optic nerve pallor was noted. Brain magnetic resonance imaging showed extensive nonenhancing white matter signal changes. The patient was diagnosed as having multiple sclerosis, for which she was prescribed interferon beta-1a, azathioprine, a single dose of natalizumab, and a course of intravenous immunoglobulin, with possible improvements. By the fifth year, cognitive change included severe expressive language difficulty; she was prescribed donepezil hydrochloride, then galantamine hydrobromide and memantine. In the seventh year, there was onset of seizures, lateralized with secondary generalization; during her entire illness, she had a total of 7 seizures. She developed chronic stiffness of all 4 extremities, some dysmetria, and increasing gait ataxia culminating in confinement to a wheelchair. Medical history was otherwise unremarkable. Family history was significant for a mother who died at age 80 years after a 7-year course of diagnosed vascular dementia, but the patient had no other affected relatives. Social history and habits were unremarkable. Examination showed an alert, nearly nonverbal woman who seemed to follow conversation, could perform simple naming and command tasks, and had a spastic quadriparesis. In the tenth year of illness, she died of pneumonia. Laboratory testing results were entirely negative, including blood tests for Huntington disease and arylsulfatase deficiency and skin biopsy for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Magnetic resonance imaging showed diffuse bilateral abnormalities including atrophy, moderately severe confluent T2-weighted fluid-attenuated inversion recovery signal hyperintensity in periventricular regions and centrum semiovale (Figure, top 2 images), and innumerable gradient-recalled echo signal hypointensities throughout the brain (Figure, bottom 2 images).
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Correct Answer: CADASIL.
What is your diagnosis?
Magnetic resonance imaging shows leukoencephalopathy and multitudinous hemosiderin deposits consistent with microhemorrhages. While the microhemorrhages could be consistent with amyloid angiopathy in isolation or Alzheimer disease, the profound motor involvement, relatively relentless course starting at age 50 years, degree of white matter signal change, and very large number of gradient-recalled echo signal hypointensities all militate against amyloid angiopathy as a cause. Multiple sclerosis does not characteristically present with microhemorrhages, and the symmetry and lack of enhancement are also atypical for multiple sclerosis. Metachromatic leukodystrophy usually does not have microhemorrhages, and the arylsulfatase level was normal. The patient was diagnosed as having CADASIL, and this disorder was confirmed by autopsy, which showed the characteristic arterial fibrotic changes with periodic acid–Schiff–positive material seen in this disorder. Skin biopsy results can be negative in a significant proportion of cases of CADASIL. However, genetic testing is diagnostic.