Dr. Angela Dispenzieri from the Mayo Clinic discusses why amyloidosis is often misdiagnosed. The complexity of the disease and commonality of symptoms are two of the reasons she examines. In addition, she offers guidance on appropriate diagnostic pathways.
Current medical education on amyloid diseases is 25 years old and materially outdated, punctuated by rapid advancement in the last five years. Hear from renowned Dr. Jeff Kelly from Scripps Research, developer of ATTR drug Tafamidis, about the current biology and how amyloid diseases such as the Systemic Amyloidoses (ATTR and AL), Parkinson’s and Alzheimer’s are today believed to be more similar than different.
There is no cure for Amyloidosis.
There are, however, an increasing number of treatment alternatives that can significantly reduce, if not eliminate, the disease and put the patient into remission. The most aggressive treatment is a stem cell transplant (SCT); sometimes referred to as a bone marrow transplant.
Stem cells are cells in the bone marrow from which all blood cells develop. This treatment aims to eradicate, typically through high-dose chemotherapy (e.g., melphalan), the faulty plasma cells which make the amyloid light chains. Once eradicated, fresh cells, harvested from the patient themselves (autologous), a donor (allogeneic), or an identical twin (syngeneic), are infused into the patient. This will help to recreate a healthy bone marrow and hopefully stop further production of the amyloid protein.
This complex treatment typically takes four to six weeks and is performed on an inpatient, outpatient, or some combination, depending on the hospital. There are meaningful differences that are important to know and incorporate into each patient’s personal situation in order to make an informed decision.
From the Healthcare Perspective
Across the country, there are multiple hospitals that perform SCTs to treat amyloidosis. While hard data is elusive, the tally of transplants at each facility, we know, is not spread evenly. We do know that Mayo Clinic (Mayo) and Boston University (BU) dominate the list and perform the majority of transplants. It may not be a surprise, then, that these two hospitals are considered amyloidosis Centers of Excellence in the U.S. They see a high volume of cases, have extensive depth and breadth of expertise, and have sophisticated diagnostic equipment. They are also the two hospitals who have pioneered performing outpatient transplants. The good news is this is evolving, with more centers across the country expanding their transplant program to treat amyloidosis.
Everyone would agree that hospitals are germ and bacteria magnets, which can be dangerous for transplant patients with low to no immune systems. BU and Mayo, for example, found patients were better able to withstand the everyday germs outside of the hospital better than the more potent ones within hospitals. This provides a strong incentive for hospitals to consider outpatient, or if they choose the inpatient route, must be ever super mindful of this reality.
There are risks with SCT, and patient safety is key. Having a patient in-house during the treatment affords the hospital maximum control during the process, while being outpatient transfers some responsibility to the caregiver, such as monitoring the patient’s temperature, food, and fluid intake. Being inpatient also affords the quickest access to experts, equipment, and drugs in the event things go awry, which does happen. Mayo has found that a meaningful percentage (38% according to Dr. Morie Gertz) of patients never need hospitalization during the SCT process; however, on the occasions where it is necessary the duration averages a handful of days.
Treating patients on an outpatient basis requires hospitals to alter their process and training, and rely on the patient and caregiver to assume a more engaged role. Without question, hospitals benefit significantly from the experience of performing high volumes of outpatient transplants. Mayo, according to Dr. Morie Gertz, performed their first SCT in March 1996, and their first outpatient SCT in September 1998. In total, they have performed 744 SCTs and currently average about 33 transplants per year. According to Dr. Vaishali Sanchorawala, BU performed their first SCT in July 1994, and their first outpatient SCT in October 1996. In total, they have performed roughly 675 SCTs for AL Amyloidosis, with an annual run rate ranging between 25 and 50. Together, these institutions have over two decades of valuable experience. According to experts, small volume and the resultant lack of experience is likely the key driver behind why hospitals elect to perform SCTs on an inpatient basis.
From the Caregiver Perspective
Caregivers play a critical role in the SCT process, working closely with the healthcare team to ensure the patient is progressing appropriately. They are so critical, in fact, that regardless of inpatient or outpatient, hospitals will not proceed with a SCT unless they are confident the patient has capable and continuous caregiver support.
The role of a caregiver varies greatly between an inpatient and outpatient process. When inpatient, the caregiver provides important emotional support, as being confined to a hospital for weeks on end can be draining and discouraging. This can range from just being present, to chatting, to light activities. Caregivers also assist in the physical need for exercise, helping and encouraging the patient to walk whenever and however many steps possible. The caregiver role may be filled by one or more persons, often impacted by the distance the hospital is from home.
Outpatient SCT procedures are significantly more demanding of caregivers. For the duration of treatment, the hospital will require the patient and caregiver(s) to be proximal to the hospital. Mayo, for example, requires patients to be within ten minutes of the hospital. Fortunately, there are many hotels, motels, inns, and homes for rent (HomeAway, VRBO) that are transplant-friendly and reasonably priced. It is 24/7 support, monitoring the patient’s key indicators, administering and monitoring meds, transporting the patient to/from the hospital daily, securing meds, shopping and preparing food, maintaining the household (e.g., laundry, sanitizing, etc.), and on and on. The list is extensive and exhaustive. Arranging for such intensive support can be a challenge. Some patients assemble a series of caregivers who rotate in/out for periods of time, others are able to secure one dedicated caregiver for the entire time, and in rare instances, the patient is able to have a team of caregivers for the duration.
Whichever caregiver structure is chosen, it is important to also consider self-care for the caregiver. Mini breaks can go a long way to help sustain their ability to meet the needs of the patient and the requirements set forth by the hospital.
From the Patient Perspective
For patients, it is all about getting through this treatment and hopefully arriving at a successful outcome. Time distills down to weeks, then days, and then when things are their most difficult, just getting through the next hour is the focus.
Having a good and capable caregiver(s) in place can help the patient focus only on themselves, knowing the caregiver will take care of everything else.
Side effects of the SCT can be multiple and vary from patient to patient. The list of effects can include fatigue, fever, diarrhea, nausea/vomiting, loss of appetite, mucositis, and hair loss. Fortunately, the healthcare team can be very helpful in mitigating these effects.
Exercise is important to ward off muscular atrophy and does improve recovery. Every step matters. Both Mayo and BU find patients do better and are home quicker if they spend less time in bed and more time moving around. In addition, patients tend to benefit from the required additional movement needed when living away from the hospital.
Emotionally, a SCT is tough. No way around that. But having distractions, whether provided by the caregiver, getting out of bed to exercise or being out and about via outpatient does contribute to an improved psyche. Having any sense of normalcy is welcome.
Cost differs greatly between inpatient and outpatient treatment, with outpatient coming in meaningfully less expensive. Anecdotal information has outpatient transplants at roughly 50% off the cost of inpatient transplants. Yet regardless of the approach, SCTs are extraordinarily expensive, and most likely patients need their insurance to sign off before treatment can begin. One of the considerations by insurance companies is which hospital the patient is proposing for treatment. During our personal experience, where we dealt with two national insurance companies, both informed us that having treatment at a Center of Excellence made a difference.
Finally, what is it really like? While situations vary widely from patient to patient, as may treatments and outcomes, hearing about a SCT straight from a patient who has been there is helpful. Having had an outpatient stem cell transplant in July 2017, hear Mackenzie’s perspective while fresh post-Mayo. Additionally, preparing for an outpatient SCT is more involved for the patient and caregiver; we have provided SCT and Post-Chemo Tips on the Resources page of our website which others may find helpful.
There is strong evidence over many years and many transplants that patient outcomes are better when performed on an outpatient basis. There are, however, notable implications for the healthcare providers, patients and caregivers, depending on which approach is chosen. Inpatient, outpatient and hybrid approaches can provide successful outcomes, but knowing these differences in advance is helpful to the decision-making process.
Morie A Gertz, M.D., M.A.C.P.
Consultant | Division of Hematology | Roland Seidler Jr. Professor Department of Medicine | College of Medicine | Mayo Distinguished Clinician
Vaishali Sanchorawala, M.D.
Professor of Medicine | Director, Autologous Stem Cell Transplant Program | Director, Amyloidosis Center
Boston Medical Center and Boston University School of Medicine
WHAT IS SPINAL STENOSIS?
Spinal stenosis is narrowing of the spinal column that causes pressure on the spinal cord, or narrowing of the openings (called neural foramina) where spinal nerves leave the spinal column.
This can develop as you age from drying out and shrinking of the disk spaces. (The disks are 80% water.) The narrowing can cause compression on nerve roots resulting in pain or weakness of the legs. If this happens, even a minor injury can cause inflammation of the disk and put pressure on the nerve. You can feel pain anywhere along your back or leg(s) that this nerve supplies.1
Symptoms often get worse slowly over time. Most often, symptoms will be on one side of the body, but may involve both legs. Symptoms include:
- Numbness, cramping, or pain in the back, buttocks, thighs, or calves, or in the neck, shoulders, or arms
- Weakness of part of a leg or arm
Symptoms are more likely to be present or get worse when you stand or walk. They often lessen or disappear when you sit down or lean forward. Most people with spinal stenosis cannot walk for a long period. More serious symptoms include:
- Difficulty or poor balance when walking
- Problems controlling urine or bowel movements
A POTENTIAL CLUE TO AMYLOIDOSIS?
Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs.
“Another very important historical clue is spinal stenosis, and actually that’s much more commonly seen in patients with ATTR than AL, and in fact, again, almost exclusively in wild type,” according to Dr. Mazen Hanna2
WHAT IS SENILE, AKA WILD-TYPE, AMYLOIDOSIS (ATTRwt)?
Amyloidosis is a generic name for a very diverse group of protein folding disorders, all characterized by creation of cross-beta-sheet fibrils. At least 30 different human proteins have been shown to form amyloid fibrils in vivo (7). Two main groups of amyloid conditions exist: systemic and localized. In the systemic conditions, deposits occur in many organs and tissues, and the diseases are usually life-threatening; in each of these diseases one out of at least 15 plasma proteins forms amyloid fibrils far from the place of parent protein synthesis. In the localized conditions, the proteins are expressed at the site of deposition (8). In both groups, fibrils usually deposit extracellularly and can form conspicuous masses that deform a tissue and interfere with its normal functions.5
Senile systemic amyloidosis (SSA), derived from wild-type transthyretin (TTR), is common in association with aging, although symptom-giving disease usually is comparably rare and affects males at least 10 times more often than women. Restrictive cardiomyopathy is the main clinical expression. However, carpal tunnel syndrome is common in SSA, and widely spread wild-type ATTR amyloid deposits at other connective tissue sites have been demonstrated (25).5
Joint cartilage and ligaments are targets of both localized and systemic amyloid. Of the systemic forms, Aβ2-microglobulin [for nomenclature, see (7)] amyloidosis is well-known to engage skeletal and joint structures in patients under hemodialysis due to renal insufficiency (9-13). Also, immunoglobulin light chain (AL) amyloidosis is known to generate a variety of symptoms from joints and skeleton, sometimes with neural lesions. Carpal tunnel syndrome is often noted in transthyretin (ATTR) and Aβ2-microglobulin amyloidosis (15–17).5
From the studies referenced therein, results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected3 and that lumbar spinal stenosis quite frequently may be a consequence of senile systemic amyloidosis [also known as wild-type amyloidosis; ATTRwt]5.
Sueyoshi T, Ueda M, Jono H, Irie H, Sei A, Ide J, Ando Y, Mizuta H. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011 Sep;42(9):1259-64. doi: 10.1016/j.humpath.2010.11.017. Epub 2011 Feb 21. PMID: 21334722.
Westermark P, Bergström J, Solomon A, Murphy C, Sletten K. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 Suppl 1:48-54. PMID: 14640042.
Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. doi:10.3109/03009734.2014.895786