Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is predominantly a disease of the peripheral nerves, heart, kidney, and eye. CNS involvement has been a marginal issue in research and the clinical setting until recently. Growing evidence shows that leptomeningeal amyloid accumulation is frequent and present from early stages of ATTRv amyloidosis. Several recent studies show CNS symptoms arise as a common late complication in patients with the V30M mutation after at least 14 years of symptomatic peripheral nerve disease. Conversely, in non-V30M patients, there are several descriptions, mostly case reports, of patients presenting with severe phenotypes of ocular and CNS dysfunction (oculoleptomeningeal amyloidosis), with little systemic involvement. This phenotype is found in rare families worldwide, associated with at least 14 mutations. In both patients with late and early onset CNS dysfunction, symptoms include transient focal neurologic episodes, hemorrhagic and ischemic stroke, cognitive decline, and cranial nerve dysfunction. Pathologically, there is severe amyloid deposition in the leptomeninges and cerebral amyloid angiopathy of leptomeningeal and penetrating vessels. These amyloid aggregates are formed mostly by CSF-produced transthyretin (TTR) and seem resistant to the available ATTRv therapies that increase the stability or reduce the production of plasma TTR. This indicates that CNS involvement will become a meaningful issue in patient management in upcoming years.
© 2021 American Academy of Neurology.