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Abstract
Background
Both hereditary transthyretin (ATTRv) amyloidosis and wildtype transthyretin (ATTRwt) amyloidosis can be associated with neurological diseases such as carpal tunnel syndrome and polyneuropathy. While ATTRv amyloidosis has been extensively studied, to date little is known about neurological complications of ATTRwt amyloidosis. In particular, the prevalence, pattern and extent of polyneuropathy and autonomic dysfunction has not been adequately investigated in the context of ATTRwt amyloidosis. To tackle this issue, we aimed to characterise the neurological presentation of ATTRwt amyloidosis and to compare between the presentations of ATTRv and ATTRwt amyloidoses.
Patients and methods
Between November 2019 and September 2020, we included 50 patients with ATTRwt amyloidosis in this cohort study. All patients presented to the amyloidosis centre in Berlin, Germany and underwent neurological, cardiological and radiological work-up including neurological examination, laboratory testing, nerve conduction studies (NCS), echocardiography and scintigraphy. Patients were screened for symptoms of autonomic dysregulation and a subgroup of patients underwent tilt-table testing for orthostatic dysregulation.
Results
The cohort included 46 men and 4 women; the mean age of the study participants was 80.6 (standard deviation [SD] ± 5.0) years. All patients showed signs of cardiomyopathy on echocardiography. Neurological examination revealed peripheral, symmetric and length-depended predominately sensory polyneuropathy in 74% (n = 37) of patients. Neuropathy impairment scores (NIS) ranged from 0 to 50 with an average score of 8.4 (SD ± 10.1) indicating mild to moderate impairment. 90% and 92% of patients were classified as FAP stage I and PND stage I, respectively. Unilateral or bilateral carpal tunnel syndrome (CTS) was present in 70% (n = 35) and spinal stenosis was seen in 11% (n = 5) of patients. We detected a low rate of autonomic symptoms with a median COMPASS-31 total score of 18.4 points (IQR 32.4 points). Additional tilt-table testing of a subgroup of 8 patients yielded negative results for orthostatic intolerance.
Conclusion
Distal-symmetric, predominantly sensory polyneuropathy is a common neurological complication in ATTRwt amyloidosis besides carpal tunnel syndrome and spinal stenosis, further substantiating the systemic character of the disease. Compared to ATTRv amyloidosis, the severity of polyneuropathy in ATTRwt amyloidosis is milder and without relevant motor involvement. Symptoms of autonomic dysfunction were not common in this cohort. Nevertheless, ATTRwt amyloidosis is a treatable disease and should be included in the differential diagnosis of sensory polyneuropathy in the elderly.
Ethical approval
This study followed ethical principles of the Declaration of Helsinki appointed from the World Medical Association in 1964. The study was approved by the local ethical research committee (reference number: EA1/188/19).
Disclosure statement
Felix Kleefeld received personal research funding for this research project by Pfizer Pharmaceuticals and travel support by Pfizer Inc., Alnylam Inc. and Akcea Therapeuticals Inc. Elise Scherret declares that she has no conflict of interest. Katrin Hahn received financial reimbursement for consulting, advisory board activities, speaker fees and/or contributions to congresses and travel support to attend scientific meetings by Akcea Therapeuticals Inc., Alnylam Pharmaceuticals Inc., Takeda Pharmaceutical Inc., Pfizer Pharmaceuticals Inc. and Swedish Orphan Biovitrum Inc. KH further received research funding by the foundation Charité (BIH clinical fellow), Alnylam Pharmaceuticals Inc., and Pfizer Pharmaceuticals. Fabian Knebel received speaker honoraria from Alnylam Inc., Pfizer Inc., and research support from Alnylam Inc and Pfizer Inc. Christoph Wetz received a speaker honorarium from Company Novartis, Pfizer and Alnylam Pharmaceuticals; and received grants/research support from Novartis. Imke Schattka received research support by Pfizer, outside the submitted work. Bettina Heidecker declares that she has no conflict of interest. Daniel Messroghli has received honoraria for speaking at symposia from Pfizer and Akcea and research funding from Pfizer. Carsten Tschöpe has received speaker fees and/or contributions to congresses from Abbott, Abiomed, Astra Zeneca, Bayer, Novartis, Pfizer, and Servier; all outside the submitted work. Gina Barzen declares that she has no conflict of interest. Holger Amthauer has received grants from Pfizer during the conduct of the study; lecture and/or personel fees from Sirtex Medical, Pfizer, Terumo, EISAI, GE, Novartis and Norgine, outside the submitted work.