Late-onset peripheral neuropathy in patients with wild type transthyretin amyloidosis (wtATTR).
TL;DR: Wild type (“senile”) transthyretin amyloid cardiomyopathy (wtATTR-CM) is an increasingly recognised cause of heart failure with normal ATTR genotype.
Abstract: Wild type (“senile”) transthyretin amyloid cardiomyopathy (wtATTR-CM) is an increasingly recognised cause of heart failure with normal ATTR genotype [1]. The frequency of wtATTR-CM is much greater ...
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TL;DR: In this article, the authors report findings from a single-centre experience of routine neuropathy screening at the time of transthyretin amyloidosis diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls.
Abstract: Background: Wild-type transthyretin amyloidosis (wtATTR) is an important cause of heart failure (HF); however, the prevalence and clinical significance of neurologic complications remains uncertain. Methods:
This analysis reports findings from a single-centre experience of routine neuropathy screening at the time of wtATTR diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls. Results:
Forty-one wtATTR patients were included, 39 (95%) males, mean age 78.4 ± 7.7 years, 22 (54%) New York Heart Association (NYHA) class III–IV HF, along with 15 age-matched controls (mean age 77.1 ± 4.2 years, 80% male). Twenty-one (51%) wtATTR patients were diagnosed with polyneuropathy, 15 (37%) with spinal stenosis, 36 (88%) with carpal tunnel syndrome (CTS) and 14 (34%) with ulnar neuropathy. Comparison diagnoses among controls were 1 (7%), 0, 1 (7%) and 3 (20%), respectively. Among patients with NYHA class III–IV HF, 16 (73%) had polyneuropathy compared with 5 (26%) with class I–II (p < 0.01), odds ratio of 7.5 (95% confidence interval 1.9–29.9). After neuropathy screening, 19 (46%) patients were offered neurologic therapy and/or additional diagnostic evaluation. This included CTS release surgery (16, 39%), neuropathic pain medication (3, 7%), nerve block (1, 2%), wrist splinting (2, 5%) and foot care (1, 2%). Spine imaging was performed for 3 (7%) patients, and deltoid muscle and sural nerve biopsy for 1 (2%) patient. Conclusions:
Screening of wtATTR patients for neurologic complications resulted in a management change for nearly half. CTS, polyneuropathy and ulnar neuropathy were common. This approach warrants consideration as part of routine assessment for newly diagnosed wtATTR patients.
8 citations
TL;DR: In this article, the authors aim to improve awareness and outcomes of hereditary transthyretin-mediated (hATTR) amyloidosis by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.
Abstract: Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.
7 citations
TL;DR: Early detection of large and small-nerve fiber damage via a comprehensive diagnostic algo was proposed in this article for transthyretin (ATTR) amyloidosis is frequently underdiagnosed, delaying effective treatment.
Abstract: Neuropathy in transthyretin (ATTR) amyloidosis is frequently underdiagnosed, delaying effective treatment. Early detection of large- and small-nerve fiber damage via a comprehensive diagnostic algo...
3 citations
TL;DR: 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.
Abstract: 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.
3 citations
TL;DR: Early diagnosis is expected to lead to more effective treatment, especially now that several medications showing improved outcomes in treatment of hATTR-neuropathy (inotersen, patisiran, tafamidis, diflunisal) and cardiomyopathy (tAFamidis).
Abstract:
2 citations
References
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TL;DR: Previously treatable only by organ transplantation, pharmaceutical therapy that slows or halts ATTR-CM progression and favorably affects clinical outcomes is now available.
509 citations
"Late-onset peripheral neuropathy in..." refers background in this paper
...The frequency of wtATTR-CM is much greater then hereditary ATTR amyloidosis, and emerging data indicate an even higher prevalence than was previously recognised [1]....
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...Wild type (“senile”) transthyretin amyloid cardiomyopathy (wtATTR-CM) is an increasingly recognised cause of heart failure with normal ATTR genotype [1]....
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TL;DR: The difference in survival, despite evidence of more myocardial disease in the senile group, suggests that heart failure in AL amyloidosis may have a toxic component, possibly related to the circulating monoclonal light chain.
Abstract: Background:Small deposits of amyloid are often found intheheartsofelderlypatients.However,extensivedepositionoftransthyretin-derivedamyloidfibrilsintheheart (senile systemic amyloidosis [SSA]) can cause heart failure. The clinical features of SSA that involve the heart are ill defined, and the condition may be overlooked as a cause of heart failure. We sought to better define the clinical,echocardiographic,andelectrocardiographicfeaturesofcardiacinvolvementinSSAandtocomparethem with the findings in patients with light chain–associated (AL) amyloidosis that affects the heart. Methods: Eighteen consecutive patients with SSA and heart failure evaluated at a tertiary referral center for the diagnosis and treatment of amyloidosis were compared with 18 randomly selected patients with AL amyloidosisthatinvolvedtheheart.Allpatientsunderwentacomplete clinical and biochemical evaluation. Echocardiogramsandelectrocardiogramswereinterpretedbyblinded investigators. Results:PatientswithSSAwereolderthanthosewithAL amyloidosis and were all male. Proteinuria (protein outputof1gper24hours)wascommoninALamyloidosis butwasnotpresentinSSA.Leftventricularwallthickness was greater in patients with SSA than those with AL amyloidosis,butdespitethickerwallsandolderage,theseverity of heart failure was less in the SSA group and the mediansurvivalwasmuchlonger(75vs11months;P=.003). Conclusions: Senile systemic amyloidosis is a disorder of elderly men and is characterized by amyloidosis clinically limited to the heart. In contrast to the rapid progression of heart failure in AL amyloidosis, SSA results in slowly progressive heart failure. The difference in survival, despite evidence of more myocardial disease in the senile group, suggests that heart failure in AL amyloidosis may have a toxic component, possibly related to the circulating monoclonal light chain. Arch Intern Med. 2005;165:1425-1429
333 citations
"Late-onset peripheral neuropathy in..." refers background or result in this paper
...The clinical presentation of wtATTR-CM is dominated by cardiac symptoms, and symptomatic neuropathy was reported in up to 12% of cases with limited description of associated neuropathy [2]....
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...None of the patients in our series had significant dysautonomia by history, similarly as previously reported by Ng who found orthostatic hypotension only in 1 of 16 patients with wtATTR-CM [2]....
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TL;DR: If TTR‐FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large‐ and small‐fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.
Abstract: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.
182 citations
"Late-onset peripheral neuropathy in..." refers background in this paper
...Interestingly, our study also demonstrates multisystemic symptoms and signs in wtATTR-CM, and each of our patients had at least 2 “red flag” signs of systemic amyloidosis in addition to neuropathy as previously described with hereditary ATTR amyloidosis [5]....
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TL;DR: In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion.
Abstract: Objectives: To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP). Methods: We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models. Results: For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin ( TTR ) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p p TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year. Conclusions: In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion.
98 citations
"Late-onset peripheral neuropathy in..." refers background in this paper
...Most of the patients in our series had mild neuropathy, and none had severe neuropathic pain or progressive weakness, contrasting the rapid progression of hereditary ATTR amyloidosis where many patients develop severe disability within 5 years from onset [3]....
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TL;DR: Idiopathic neuropathy is one of the most common clinical problems encountered in general medical and neurological practices, and could represent an ideal population in which to examine potential therapies for diabetes and obesity related neuropathies.
Abstract: Idiopathic neuropathy is one of the most common clinical problems encountered in general medical and neurological practices, accounting for up to 40% of all neuropathies in referral series. Several groups have reported an elevated prevalence of impaired glucose tolerance (IGT) in idiopathic neuropathy subjects, although the only carefully conducted case-control study suggested hypertriglyceridemia was a more important risk factor. The nature of the relationship between IGT and neuropathy is a subject of active debate. An evolving literature suggests metabolic syndrome, particularly dyslipidemia and obesity, are potent neuropathy risk factors for both idiopathic and diabetic neuropathy patients. Once established, diabetic neuropathy is likely to be very difficult to reverse. IGT-associated neuropathy, however, may be more amenable to therapy and could represent an ideal population in which to examine potential therapies for diabetes and obesity related neuropathies. Further research is needed to better define the epidemiological relation between IGT, metabolic syndrome, and neuropathy, its underlying pathophysiology, and to develop appropriate surrogate measures and clinical trials strategies.
49 citations
"Late-onset peripheral neuropathy in..." refers result in this paper
...Neuropathy in patients with impaired glucose tolerance has been attributed to metabolic syndrome, and only one of our patients fulfilled the criteria for metabolic syndrome suggesting that impaired glucose tolerance was probably not the cause of neuropathy in most of our patients [4]....
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