**4.1 Diagnosis of ATTRwt**

It should be noted that significant amount of ATTRwt deposition, not a mere presence, is needed to establish a pathogenic role [77]. ATTRwt is most commonly diagnosed in the setting of a late onset cardiomyopathy. Tissue deposition of amyloid with Congo Red staining and subsequent immunohistochemical or proteomic analysis of the amyloid deposits along with a TTR gene sequencing (which does not show a pathogenic Mutation) are usually needed to diagnose ATTRwt. On the other hand, Technetium-labeled bone scintigraphy tracers are long to be known to be able to detect myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has been increasingly. In a recent study on 857 patients with histologically proven cardiac amyloid (374 with endomyocardial biopsies) and 360 patients with nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives exclusively due to cases with AL amyloidosis [29]. Therefore cardiac ATTR can be diagnosed without a tissue biopsy and exclusion of AL amyloidosis based on serum and urine immunofixation and free lambda and kappa levels. Similar to the situation with fATTR, high prevalence of MGUS in ATTRwt poses a diagnostic challenge. About one fourth to 50% of patients with ATTRwt have a monoclonal gammopathy in the serum or urine and ~10% have a high serum kappa/lambda ratio [30, 78, 79]. It should be noted that abdominal fat pad aspiration and biopsy have a low sensitivity for ATTRwt, 12–14% on some of the previous studies [80, 81], although using abdominal fat pad biopsy, sensitivity of 73% has also been reported in another study [82].

### **4.2 Neurological manifestations of ATTRwt**

ATTRwt is generally not associated with a polyneuropathy. A previous report suggested ATTRwt as a cause of a rapidly progressive neuropathy in an elderly woman; amyloid deposits were present in the gastrocnemius, but not the sural nerve of that patient [83]. On the other hand, ATTRwt is rather commonly associated with late onset musculoskeletal problems, particularly carpal tunnel syndrome and lumbar spinal stenosis, but overall it is underdiagnosed. ATTRwt deposits have been demonstrated in about one third of tenosynovial tissues obtained during carpal tunnel release operation in elderly patients [84, 85], as well as in 30–45% of the resected tissues harvested during decompression surgeries for lumbar spinal stenosis [77, 86].

The ATTRwt deposits are frequently minimal and may not be important from the pathogenesis standpoint [77]. On the other hand, more prominent amyloid

**101**

*Neurological Manifestations of Transthyretin-Related Amyloidosis*

deposition may play a role in spinal stenosis as they cause increased thickness of ligamentum flavum or abnormal spinal stability [86]. Examination of tenosynovial tissue on 100 patients with idiopathic CTS showed positive Congo Red staining on 34 patients, all also positively staining with anti TTR antibody with negative gene sequencing, consistent with ATTRwt [84]. On the other hand, in a single center study involving 31 ATTRwt patients, CTS was the most common presenting symptom in more than 50% of the patients [87]. In another recent prospective study on 98 patients with idiopathic CTS in men >60 year and women >50, who underwent decompressive surgery, amyloid deposits were found in 10 patients, 5 of which turned out to be due to ATTRwt [88]. Spinal cord compression secondary to ATTRwt has also been rarely reported [89, 90]. Myopathy is rarely reported as a feature of ATTRwt, but in the author's opinion it is underdiagnosed. We previously reported a patient who presented with bent spine syndrome due to ATTRwt related myopathy affecting the thoracic paraspinal muscles [91]. That patient succumbed as the result of consequences of cardiomyopathy and a cardio-

Although TTR stabilizers and suppressors of gene expression will likely suppress ATTRwt deposition, there are no current FDA approved disease modifying therapies for ATTRwt and the management remains to be symptomatic, such as medical treatment of heart failure and arrhythmias, including insertion of defibrillator/ pacemaker, and heart transplantation if necessary. Treatment of neuromuscular complications remains to be symptomatic as well, i.e. decompression surgeries of myelopathy and lumbar spinal stenosis and carpal tunnel syndrome release. The reasons for lack of disease modifying treatments include the fact that ATTRwt is underdiagnosed and the natural history of its neuromuscular complications is unknown. Furthermore, ATTRwt is a disease of older population and neuromuscular complications are likely overshadowed by other medical comorbidities specially heart disease [78], and therefore the effect of disease modifying treatments would be

Familial amyloid polyneuropathy is a rare, but treatable cause of neuropathy, diagnosis in an early stage is essential to establish disease modifying treatment at a stage which the disability can be prevented from progression or potentially reversed. Diagnosis should be suspected when red-flag symptomatology is present in a patient with neuropathy; and can possibly be established by sequencing of transthyretin gene. Musculoskeletal disease such as carpal tunnel syndrome and spinal stenosis are early manifestations and underdiagnosed causes of wild-type transthyretin amyloidosis. Increased cardiac uptake on nuclear imaging studies is a sensitive, widely available diagnostic modality for early diagnosis of familial and

Dr. Rezania has received funding from Amyotrophic Lateral Sclerosis Association (ALSA) and National Institute of Neurological Disorders and Stroke; has served on the advisory boards of Alnylam, Alexion and MT Pharma; has received honoraria for

*DOI: http://dx.doi.org/10.5772/intechopen.84470*

embolic stroke.

difficult to assess.

**5. Conclusions**

wild-type transthyretin amyloidosis.

**Conflict of interest**

**4.3 Treatment of ATTRwt**

*Neurological Manifestations of Transthyretin-Related Amyloidosis DOI: http://dx.doi.org/10.5772/intechopen.84470*

deposition may play a role in spinal stenosis as they cause increased thickness of ligamentum flavum or abnormal spinal stability [86]. Examination of tenosynovial tissue on 100 patients with idiopathic CTS showed positive Congo Red staining on 34 patients, all also positively staining with anti TTR antibody with negative gene sequencing, consistent with ATTRwt [84]. On the other hand, in a single center study involving 31 ATTRwt patients, CTS was the most common presenting symptom in more than 50% of the patients [87]. In another recent prospective study on 98 patients with idiopathic CTS in men >60 year and women >50, who underwent decompressive surgery, amyloid deposits were found in 10 patients, 5 of which turned out to be due to ATTRwt [88]. Spinal cord compression secondary to ATTRwt has also been rarely reported [89, 90]. Myopathy is rarely reported as a feature of ATTRwt, but in the author's opinion it is underdiagnosed. We previously reported a patient who presented with bent spine syndrome due to ATTRwt related myopathy affecting the thoracic paraspinal muscles [91]. That patient succumbed as the result of consequences of cardiomyopathy and a cardioembolic stroke.

#### **4.3 Treatment of ATTRwt**

*Amyloid Diseases*

walls of small arteries [74].

**4.1 Diagnosis of ATTRwt**

reported in another study [82].

lumbar spinal stenosis [77, 86].

**4.2 Neurological manifestations of ATTRwt**

deposition [74]. In fATTR deposits are predominantly localized in the pericardium and surrounding muscle fascicles, on the other hand, they have patchy plaque-like shapes and mostly appear inside the ventricular wall in ATTRwt cases. Differences also exist between the shape of deposited amyloid fibrils between fATTR and ATTRwt in electron microscopy: in fATTR, long, straight fibrils are arranged in parallel, whereas short, rigid fibrils with haphazard arrangement are noted in ATTRwt, with endocardial region more involved than epicardium [74]. ATTRwt also involves other organs, often subclinically. In the pathological study by Ueda, et al., amyloid deposits were noted in bladder in 5/6 cases; deposits in the thyroid, pancreas, liver, gallbladder, adrenal gland, and gastrointestinal tract were mainly located in the

It should be noted that significant amount of ATTRwt deposition, not a mere presence, is needed to establish a pathogenic role [77]. ATTRwt is most commonly diagnosed in the setting of a late onset cardiomyopathy. Tissue deposition of amyloid with Congo Red staining and subsequent immunohistochemical or proteomic analysis of the amyloid deposits along with a TTR gene sequencing (which does not show a pathogenic Mutation) are usually needed to diagnose ATTRwt. On the other hand, Technetium-labeled bone scintigraphy tracers are long to be known to be able to detect myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has been increasingly. In a recent study on 857 patients with histologically proven cardiac amyloid (374 with endomyocardial biopsies) and 360 patients with nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives exclusively due to cases with AL amyloidosis [29]. Therefore cardiac ATTR can be diagnosed without a tissue biopsy and exclusion of AL amyloidosis based on serum and urine immunofixation and free lambda and kappa levels. Similar to the situation with fATTR, high prevalence of MGUS in ATTRwt poses a diagnostic challenge. About one fourth to 50% of patients with ATTRwt have a monoclonal gammopathy in the serum or urine and ~10% have a high serum kappa/lambda ratio [30, 78, 79]. It should be noted that abdominal fat pad aspiration and biopsy have a low sensitivity for ATTRwt, 12–14% on some of the previous studies [80, 81], although using abdominal fat pad biopsy, sensitivity of 73% has also been

ATTRwt is generally not associated with a polyneuropathy. A previous report suggested ATTRwt as a cause of a rapidly progressive neuropathy in an elderly woman; amyloid deposits were present in the gastrocnemius, but not the sural nerve of that patient [83]. On the other hand, ATTRwt is rather commonly associated with late onset musculoskeletal problems, particularly carpal tunnel syndrome and lumbar spinal stenosis, but overall it is underdiagnosed. ATTRwt deposits have been demonstrated in about one third of tenosynovial tissues

obtained during carpal tunnel release operation in elderly patients [84, 85], as well as in 30–45% of the resected tissues harvested during decompression surgeries for

The ATTRwt deposits are frequently minimal and may not be important from the pathogenesis standpoint [77]. On the other hand, more prominent amyloid

**100**

Although TTR stabilizers and suppressors of gene expression will likely suppress ATTRwt deposition, there are no current FDA approved disease modifying therapies for ATTRwt and the management remains to be symptomatic, such as medical treatment of heart failure and arrhythmias, including insertion of defibrillator/ pacemaker, and heart transplantation if necessary. Treatment of neuromuscular complications remains to be symptomatic as well, i.e. decompression surgeries of myelopathy and lumbar spinal stenosis and carpal tunnel syndrome release. The reasons for lack of disease modifying treatments include the fact that ATTRwt is underdiagnosed and the natural history of its neuromuscular complications is unknown. Furthermore, ATTRwt is a disease of older population and neuromuscular complications are likely overshadowed by other medical comorbidities specially heart disease [78], and therefore the effect of disease modifying treatments would be difficult to assess.

### **5. Conclusions**

Familial amyloid polyneuropathy is a rare, but treatable cause of neuropathy, diagnosis in an early stage is essential to establish disease modifying treatment at a stage which the disability can be prevented from progression or potentially reversed. Diagnosis should be suspected when red-flag symptomatology is present in a patient with neuropathy; and can possibly be established by sequencing of transthyretin gene. Musculoskeletal disease such as carpal tunnel syndrome and spinal stenosis are early manifestations and underdiagnosed causes of wild-type transthyretin amyloidosis. Increased cardiac uptake on nuclear imaging studies is a sensitive, widely available diagnostic modality for early diagnosis of familial and wild-type transthyretin amyloidosis.

#### **Conflict of interest**

Dr. Rezania has received funding from Amyotrophic Lateral Sclerosis Association (ALSA) and National Institute of Neurological Disorders and Stroke; has served on the advisory boards of Alnylam, Alexion and MT Pharma; has received honoraria for

#### *Amyloid Diseases*

giving speeches from Alexion, MT Pharma Tanabe, Kabafusion, Option Care, Sanofi-Genzyme, and American Association of Neuromuscular and Electrodiagnostic Medicine; has received loyalties from Medlink.
