Functional Impairments of Amyloidosis Patients: Physical Therapy Assessment

Abstract

Amyloidosis is a rare, systemic disease that can result in significant functional impairment. Specific guidelines for the rehabilitation assessment of amyloidosis patients have yet to be established. The purpose of this study was to identify functional deficits and assess differences based on disease type, organ involvement, age, and gender of patients with amyloidosis. Materials and Methods: The multidisciplinary Comprehensive Amyloidosis Clinic (CAC) at Ohio State University (OSU) has developed structured assessment guidelines for amyloidosis patients. A retrospective, single-institution review of patients assessed in CAC between December 2017 and April 2020 was performed. Outcome measure data from the Timed Up and Go (TUG), 30 s sit-to-stand, and physical function portion of the SF 36 were gathered by chart review. Comparisons were made between CAC patient scores and normative data. Kruskal–Wallis tests were used to compare scores across the disease types (light chain, transthyretin wild-type, and hereditary variant transthyretin) and the Mann–Whitney U test was used for pairwise comparisons within disease types and cardiac involvement. Linear regression models were used to assess associations between patient characteristics (including age, gender, disease type, and cardiac involvement) and performance scores. Results: Data from sixty-four patients was evaluated. On the 30-s sit-to-stand test, patients with light chain amyloidosis performed 3.32 fewer repetitions than patients with transthyretin wild-type, p = 0.03. Patients with cardiac involvement had 2.55 fewer repetitions than patients without cardiac involvement, p = 0.03. Older patients were found to have slower TUG performance, and a 10-year increase in age was associated with an 11% increase in TUG scores. Conclusions: Findings indicate patients with light chain amyloidosis and patients with cardiac involvement, when compared to other amyloidosis patients, present with more physical impairments.

1. Introduction

Amyloidosis is a multisystem condition characterized by the deposition of insoluble, misassembled fibril proteins that interfere with normal tissue structure and function. These protein deposits affect the normal organ tissues of different systems within the body causing both physical and functional impairments. Most commonly, the depositions appear in the heart, kidneys, connective tissues, and peripheral nerves [1,2,3,4]. The proteins most frequently involved in systemic amyloidosis are light chain (AL) and transthyretin, either a wild-type (ATTRwt) or hereditary variant (ATTRv).

Due to the rare nature of this disease and the initial presentation of amyloidosis symptoms consistent with other diagnoses (i.e., carpal tunnel syndrome, peripheral neuropathy, congestive heart failure, or renal failure) accurate diagnosis is often delayed. Increased time to testing for accurate diagnosis leads to the delay of medical therapies, further impairments in functional mobility, and a decrease in the health-related quality of life.

While amyloidosis itself interrupts normal tissue function, treatment-related toxicities can also impact a patient’s health-related quality of life [5]. Functional assessments performed at the initial diagnosis and throughout treatment allow providers to monitor symptoms and refer patients to physical therapy.

Physical therapy treatment of patients with other hematologic diagnoses, specifically multiple myeloma (MM), has been more closely examined. MM is a cancer of plasma cells and the majority of the patients present with bone involvement and anemia. Many MM patients develop secondary light chain amyloidosis during their disease course. Physical therapy has been shown to enhance the quality of life of MM patients and is recommended as a part of cancer rehabilitation for MM patients [6,7,8]. Physical therapy treatment is indicated in patients with MM and amyloidosis.

The Comprehensive Amyloidosis Clinic (CAC) at Ohio State University (OSU) is a collaborative multidisciplinary clinic that allows a patient to see neurology, nephrology, cardiology, hematology, and physical therapy in one 3-h visit. The multisystem nature of this disease indicates the need for multidisciplinary care [9]. Specific guidelines for the physical therapy assessment and rehabilitation of amyloidosis patients have yet to be established.

This study aimed to identify amyloidosis patients’ physical impairments and functional mobility deficits across different disease types, organ involvement, age, and gender.

2. Materials and Methods

A retrospective, single-institution review of patients who attended the CAC between December 2017 and April 2020 was performed. The Institutional Review Board at OSU approved the study. The study complies with the Declaration of Helsinki and was approved by OSU IRB #2020C0113.

Patients were included if they had a definite amyloidosis diagnosis including light chain (AL), wild-type transthyretin (ATTRwt), and hereditary variant amyloidosis (ATTRv). All outcome measures were completed and documented at the time of the first visit to the clinic. The patients were identified to have either heart, kidney, nerve, or multiple system involvement. Patients were excluded if they did not have a full physical therapy assessment including all outcome measures at the time of their first visit to the clinic. Patients who were still undergoing testing for amyloidosis at the time of the visit to the Comprehensive Amyloidosis Clinic were also excluded. Data were collected on patient age, gender, disease type, and organ involvement.

The Outpatient Oncology Rehabilitation Department at OSU has structured specific guidelines to assess functional impairments in the CAC to improve quality of life and functional mobility and reduce the risk of physical decline. Physical therapy evaluation includes subjective reporting from the patient of their functional limitations, home setup, goals for rehabilitation, range of motion, and manual muscle testing [10,11]. Objective outcome assessments include the 30 s sit-to-stand and Timed Up and Go (TUG) tests [12]. The 30-s sit-to-stand test has been found to be valid and reliable in assessing the lower body strength of community-dwelling older adults [12]. The Timed Up and Go test (TUG) is strongly correlated to functional mobility and increased time to perform this test indicates an increased fall risk [13]. The physical function section of the Short Form 36 was chosen to provide a qualitative value for perceived health [14]. Details of characteristics of the 30 s sit-to-stand, TUG, and SF 36 as well as data on their reliability and validity have been described by Jones, Shumway–Cook, and Brazier, respectively [12,13,14]. These scores from the first visit to the clinic were compared to age and gender established normative values.

Comparisons of TUG and 30 s sit-to-stand performance, and SF 36 physical function scores were analyzed between patient ages, male and female patients, light chain amyloid and wild-type amyloidosis, hereditary and wild-type as well as cardiac involvement and no cardiac involvement.

Statistics

Patient characteristics were summarized using the medians and ranges, or frequencies and percentages, depending on the data type. The performance scores were presented using medians and ranges and compared among disease types using the Kruskal–Wallis test;the Mann–Whitney U test was used for the pairwise comparisons within disease types as well as by cardiac involvement. The differences from the established normative values by age and gender were calculated and compared similarly. Multiple linear regression models were used to assess the associations between patient characteristics (including age, gender, disease type, and cardiac involvement) and performance scores. One AApoAIV patient was excluded from the modeling. Due to the skewed distribution of TUG scores, inverse transformation and natural log transformation were conducted before running the linear regression models. The distribution of residuals was examined to check on the normality assumptions. All the tests were 2-sided with a significance level of 0.05. Analyses were performed in STATA (version 16, StataCorp, College Station, TX, USA).

3. Results

3.1. Patient Characteristics

From December 2017 to April 2020, of the 81 patients considered, 64 patients were included in the study. The seventeen patients excluded did not have all outcome measures collected at the time of the first visit to the CAC. The median age was 69 years (range: 29–95 years). The patients were predominantly (62.5%) male. Most of the patients included had ATTRv (40.6%) followed by ATTRwt (32.8%). AL comprised 25% of the patient population. One patient included had AApoAIV subtype amyloidosis and presented with symptoms of a typical amyloidosis patient.

Upon examination of the raw data, those patients younger than 60 years presented with neuropathy as the only symptom of their amyloidosis. When compared to patients over 70 years in this study, neuropathy was less likely to be the only symptom. In those over the age of 70 years, if neuropathy was present, another organ system was also involved.

A total of 25 patients (39.1%) had cardiac involvement as their only symptom. Multiple organ system involvement was present in 19 patients (29.7%), followed by peripheral neuropathy in 13 patients (20.3%). Only kidney involvement was seen in 6 patients (9.4%) and 1 patient presented with pulmonary involvement (

Table 1. Patient Characteristics.

	N = 81	%
Excluded	17
Patient data analyzed	64
Age (years), median, range	69	29–95
<60	12	18.8
60–64	9	14.1
65–69	16	25.0
70–74	5	7.8
75–79	14	21.9
80–84	6	9.4
85–90	0	0
>90	2
Gender
Female	23	35.9
Male	41	62.5
M (M to F transgender)	1	1.5
Disease Type
Amyloidosis (AApoAIV subtype)	1	1.5
Hereditary Amyloidosis	26	40.6
Light Chain Amyloidosis	16	25
Wild-type Amyloidosis	21	32.8
Organ involvement
Cardiac	25	39.1
Kidney	6	9.4
Multiple organ involvement	19	29.7
Peripheral neuropathy	13	20.3
Pulmonary	1	1.5

).

3.2. Physical Therapy Assessment

The 30 s sit-to-stand, TUG, and SF 36 were measured in all patients with the medians and ranges at 11 (4–22), 9.5 (5.9–54.7), and 60 (5–100), respectively.

Table 2. Comparison of performance scores among disease type and organ involvement.

		Original Score						Difference from Normative (Original Score-Normative)
	n	SF36		30 s Sit to Stand		TUG		30 s Sit to Stand: diff		TUG: diff
Disease Type		Median	Range	Median	Range	Median	Range	Median	Range	Median	Range
Amyloidosis, AApoAIV subtype	1	85		12		8.38		−3.2		1.08
Hereditary Amyloid	26	60	20–100	11.5	4–17	9	5.9–38.92	−2.5	−9.5–3.5	1.8	−1.42–25.42
Light Chain Amyloid	16	37.5	5–100	10	7–21	10	5.98–15.44	−4	−7–6.5	1.92	−2.12–7.2
Wild Type TTR Amyloid	21	65	5–100	12	7–22	10	6.2–54.66	−2.4	−6–9	0.42	−12.18–47.86
p-values:
Overall		0.32		0.7		0.82		0.35		0.48
Light Chain Amyloid vs. Wild Type		0.19		0.47		0.79		0.17		0.26
Hereditary Amyloid vs. Wild Type		0.97		0.83		0.77		0.27		0.44
Hereditary Amyloid vs. Light Chain		0.19		0.47		0.52		0.88		0.57
	n	SF36		30 Seconds Sit to Stand		TUG		30 Seconds Sit to Stand		TUG
Organ Involvement
Cardiac	25	55	5–95	10	7–17	10	6.4–54.66	−3.4	−6.4–3	1.9	−12.18–47.86
Non-cardiac	39	60	10–100	12	4–22	9	5.9–38.92	−2.5	−9.5–9	1.7	−9.6–25.42
p-value		0.71		0.2		0.44		0.7		0.9

shows the medians and ranges of physical therapy assessment scores for different disease types. There was no difference overall for any of the assessments and assessment scores among disease types when performing pairwise comparisons. In addition, scores for physical therapy assessments were not significantly different comparing patients with cardiac versus non-cardiac involvement. The differences from the established normative values by age and gender were compared and showed no significant difference by disease type or cardiac involvement (data not shown).

The multiple linear regression modeling on the associations between patient characteristics and performance scores showed that the SF 36 scores had no significant associations with age, gender, disease type, or organ involvement. 30-s sit-to-stand showed no differences based on the patient’s age or gender. However, patients with AL had lower performance on the 30-s sit-to-stand with a coefficient of −3.32 (95% CI: (−6.21 to −0.43), p = 0.03) compared to the wild-type TTR amyloidosis patients. Patients with cardiac involvement performed significantly worse than those without cardiac involvement on the 30 s sit-to-stand, with a coefficient of −2.55 (95% CI: (−4.91 to −0.02), p = 0.03). There were no significant differences in performance on the 30-s sit-to-stand test among ATTRv versus ATTRwt patients. The distributions of the residuals from the multiple linear regression models were approximately normal.

The outcomes expected with TUG performance were demonstrated in this clinic population. The linear regression models with either inversed TUG scores or log-transformed TUG scores showed that increasing age was associated with increased TUG scores. The log-transformed modeling showed increasing age to be associated with an increased log of TUG score with a coefficient of 0.01 (95% CI: 0.001–0.02, p = 0.04). A 10-year increase in age was associated with an 11% increase in TUG scores. No differences in TUG scores were observed based on either gender or disease type.

4. Discussion

No significant trends or differences were presented in our group of patients when age, gender, disease type, or organ involvement were examined. This may be related to the wide range of ages of the patients and the severity of the disease at the time of diagnosis. Additionally, patients are referred to the CAC at different points in their care. Amyloid and steroid myopathy are addressed with a referral for physical therapy treatment or a home exercise program prescription based on patient presentation and level of care. The ability to perform the tasks listed on the physical function portion of the SF 36 may be limited due to other co-morbidities. Patients with amyloidosis, specifically those with cardiac involvement, have a lower health-related quality of life (HRQoL) [15]. The information collected by this questionnaire related to HRQoL is of great value for the care of the individual patient. Understanding this information allows for patient-centered treatments as well as a way to monitor impact of the symptom burden on the patient’s daily living [2].

The number of sit-to-stand repetitions performed in 30 s in patients with AL was significantly lower than those with ATTRwt. Additionally, those with exclusively cardiac involvement had a significantly lower performance when compared to those with other organ system involvement in their disease. “Cardiac involvement in AL occurs in approximately 50% of patients” [16]. AL patients presenting with cardiac involvement and symptoms of heart failure have the greatest risk of morbidity and mortality [12]. Performance at this reduced level indicates reduced functional lower extremity strength, increases the risk for falls, and increases the need for caregiver assistance. Referral for physical therapy intervention early in the diagnosis process is indicated to prevent functional decline.

The TUG is a commonly used tool to assess healthy, community-dwelling older adults’ risk for falls. The normative data demonstrate performance on the TUG declines as people age [13]. Patients examined in the CAC demonstrate scores consistent with this data. As the patients increase in age, the time to complete the TUG increases, demonstrating an increased risk for falls.

While it is widely known that peripheral neuropathy can increase the risk for falls, in this study, the presence of only neuropathy was not directly associated with impaired performance on the assessments. This may be related to the small sample size of that group and the presence of neuropathy as a symptom in the multiple organ involvement group.

When examining the MM patient population, many are older and have multi-organ complications from the disease itself as well as treatment. Coleman et al. examined the feasibility of exercise during treatment for MM. The patients who performed the exercise program gained muscle strength and showed a decrease in fatigue. These results can be applied to those with amyloidosis, as many MM patients develop amyloidosis. Thus, further supporting the role of physical therapy treatment as a component of care [7].

Study Limitations

Overall, the number of patients in this study is small, as amyloidosis is a rare, underdiagnosed disease. This may have limited our power to detect some of the associations between patient characteristics and performance scores. As the clinic continues to grow, larger sample sizes are anticipated. Further, the sample size was affected by the number of patients who were excluded due to receiving physical therapy at the time of the first clinic visit. In addition, patients seen in the CAC clinic include a wide range of ages. Based on age alone, great diversity in functional mobility abilities would be expected. For the outcome tools used in this clinic, there are no established norms for patients younger than age 60. As patients age, the number of co-morbidities that affect physical function and mobility increases. Teasing out the specific underlying cause of patient symptoms in the presence of amyloidosis and these other conditions can be difficult.

The outcome tool scores examined for this study were taken from the first visit to the CAC. This may not have been the first visit with an amyloidosis physician or prior to the initiation of pharmacologic amyloidosis therapies. Some patients had received cardiac rehabilitation prior to their first visit to the clinic; this has the potential to improve physical performance on outcome tool scores. These factors may indicate the values are not a true baseline. We are following patients and gathering data on their performance as they go through physical therapy and attend CAC visits for future studies.

5. Conclusions

Patients with amyloidosis, especially AL and those with cardiac involvement, demonstrate significantly impaired functional mobility. Limited research exists examining the role of physical therapy for treatment of amyloidosis. This study identifies significant physical function impairments and supports the possible need for a physical therapy assessment and intervention in the care of these patients.