A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction.

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

Novel imaging techniques using 18 F-florbetapir PET/MRI can guide fascicular nerve biopsy in amyloid multiple mononeuropathy.

BACKGROUND: Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). METHODS: The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. RESULTS: Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. CONCLUSIONS: 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

Chronic inflammatory demyelinating polyradiculoneuropathy-Diagnostic pitfalls and treatment approach.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients' ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment-refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy.

OBJECTIVE: Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. METHODS: Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. RESULTS: There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. INTERPRETATION: Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology. Ann Neurol 2019;85:560-573.

Acquired and inherited amyloidosis: Knowledge driving patients' care.

Until recently, systemic amyloidoses were regarded as ineluctably disabling and life-threatening diseases. However, this field has witnessed major advances in the last decade, with significant improvements in therapeutic options and in the availability of accurate and non-invasive diagnostic tools. Outstanding progress includes unprecedented hematological response rates provided by risk-adapted regimens in light chain (AL) amyloidosis and the approval of innovative pharmacological agents for both hereditary and wild-type transthyretin amyloidosis (ATTR). Moreover, the incidence of secondary (AA) amyloidosis has continuously reduced, reflecting advances in therapeutics and overall management of several chronic inflammatory diseases. The identification and validation of novel therapeutic targets has grounded on a better knowledge of key molecular events underlying protein misfolding and aggregation and on the increasing availability of diagnostic, prognostic and predictive markers of organ damage and response to treatment. In this review, we focus on these recent advancements and discuss how they are translating into improved outcomes. Neurological involvement dominates the clinical picture in transthyretin and gelsolin inherited amyloidosis and has a significant impact on disease course and management in all patients. Neurologists, therefore, play a major role in improving patients' journey to diagnosis and in providing early access to treatment in order to prevent significant disability and extend survival.

[Diagnostics of polyneuropathies]. / Diagnostik bei Polyneuropathien.

The diagnosis of polyneuropathy (PNP) is based on the anamnesis and description of complaints of the patient and clinical findings. The type of distribution as well as known diseases and drug toxic factors can provide indications. Electromyography and electroneurography can be used to differentiate between axonal and demyelinating PNP. The laboratory examinations are initially directed towards frequent and treatable causes. These are then expanded depending on the suspected diagnosis. Analysis of cerebrospinal fluid (CSF) is facultative and should be carried out when there is a suspicion of a certain form of PNP with CSF findings indicative of the diagnosis. Nerve biopsy is indicated when the etiology of a severe or progressive PNP cannot be clarified by less invasive means and can have consequences for the treatment. A genetic investigation can be meaningful with a positive family anamnesis or with typical signs of hereditary PNP. Depending on the neuropathy and context, the diagnostic approach is structured differently. The special diagnostics for small fiber neuropathy and amyloid neuropathy as well as for diabetes and alcohol abuse are dealt with in detail in this article. Numerous cases of polyneuropathy remain unexplained and regularly have a favourable prognosis.

Diagnosis of amyloid neuropathy.

Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.

Neurophysiological techniques to detect early small-fiber dysfunction in transthyretin amyloid polyneuropathy.

INTRODUCTION: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is characterized by early selective involvement of small nerve fibers. Initial clinical diagnosis is complicated by psychosocial factors. We evaluated diagnostic accuracy of sural sensory nerve action potentials, plantar sympathetic skin response (SSR), and cortical laser-evoked potentials (LEP) to dorsal foot stimulation in the early diagnosis of TTR-FAP. METHODS: Sixty-three subjects with TTR-FAP (Val30Met) mutation were split into 2 groups (asymptomatic carriers and early-symptomatic patients) and compared with 33 healthy controls. RESULTS: The diagnostic accuracy of plantar SSR amplitude and LEP N2 latency was similar; all had very high specificity (94 to 97%) but low sensitivity (22 to 32%) in distinguishing controls from carriers and early-symptomatic patients. No control had abnormal results on both tests. CONCLUSIONS: Plantar SSR and LEPs have similar diagnostic performance in detecting small-fiber dysfunction in early TTR-FAP; we propose that both tests should be used to investigate this population. Muscle Nerve 49: 181-186, 2014.

Clinicopathological Features of Amyloid Neuropathy: A Four Decade Experience.

BACKGROUND: Peripheral neuropathy is one of the manifestations of primary or familial amyloidosis. Published studies from India are limited. MATERIALS AND METHODS: We reviewed the clinical and pathological features of amyloid neuropathy diagnosed at our Institute over the last 39 years. RESULTS: Fifty-five cases of amyloid neuropathies were diagnosed between 1981 and 2019, constituting 0.28% of peripheral nerve biopsies (55/19,081). Age at presentation ranged from 24 to 81 years (mean-48 years) with male preponderance [M:F = 3.58:1]. Duration of symptoms at presentation varied from 3 months to 10 years (mean-2.31 years). Majority presented with small fiber neuropathy (85%). Pure sensory symptoms predominated in 23%, while 72% had sensorimotor neuropathy and 35.8% had autonomic involvement, with isolated autonomic failure in one patient. Amyloid neuropathy was clinically suspected in 22.6% of nonfamilial cases. Familial amyloid neuropathy was suspected in eight patients. Genetic testing detected ATTR and gelsolin mutation in one each of tested patients. Nerve biopsies revealed characteristic birefringent amyloid deposits stained mahogany brown by Congo red predominantly surrounding endoneurial microvessels (34.5%), also in perineurium and epineurium in 25.45% cases. Preferential loss of small diameter myelinated fibers was noted. Axonal degeneration or regeneration was conspicuously absent. CONCLUSION: Amyloid neuropathy is uncommon (0.28% of nerve biopsies in our series). Nerve biopsy is essential for the diagnosis. We report our experience of amyloid neuropathy and underscore the importance of making an assiduous search for amyloid deposits in the appropriate setting. Awareness of this entity is important for early diagnosis in the light of emerging therapeutic advances.

TTR-related amyloid neuropathy: clinical, electrophysiological and pathological findings in 15 unrelated patients.

Familial amyloid polyneuropathy (FAP) is a rare condition caused by mutations of the transthyretin (TTR) gene and it is generally characterized by a length-dependent polyneuropathy affecting prevalently the small fibers. We reviewed clinical, electrophysiological and pathological findings of 15 unrelated patients with genetically confirmed TTR-FAP. All patients presented a progressive sensory-motor polyneuropathy. Pathological findings were negative for amyloid deposits in about half of the cases. Sequence analysis of TTR gene revealed the presence of three different mutations (p.Val30Met, p.Phe64Leu, and p.Ala120Ser). The p.Val30Met was the most frequently identified mutation and it often occurred in apparently sporadic cases. Conversely, the p.Phe64Leu generally presented in a high percentage of familial cases in patients coming from Southern Italy. Clinicians should consider, to avoid misdiagnosis, the screening for TTR mutations in patients presenting with progressive axonal polyneuropathy of undetermined etiology, including apparently sporadic cases with pathological examinations negative for amyloid deposition.

Amyloid neuropathies.

PURPOSE OF REVIEW: As amyloid neuropathies have benefited from recent major progress, this review is timely and relevant. RECENT FINDINGS: The main recent articles on amyloid neuropathy cover its description, methods for diagnosis and therapies. Varied clinical presentations are described in transthyretin (TTR)-familial amyloidosis with polyneuropathy (FAP) and light chain amyloid neuropathy. Mass spectrometry is able to identify the biochemical nature of amyloidogenic protein in nerve biopsy and skin biopsy samples for diagnosis of small fiber polyneuropathy. Both nerve biopsy and TTR gene sequencing are important to identify sporadic cases of amyloid neuropathy. Nerve biopsy is useful in demonstrating the amyloid origin of neuropathies developing after domino liver transplant recipients. Liver transplantation improves long-term survival in Met30 TTR-FAP. Factors recognized as leading to cardiomyopathy progression or heart involvement after liver transplantation are late disease onset and fibril composition. Combined heart and liver transplantation is recommended in severe restrictive cardiomyopathy. Antiamyloid drugs are emerging: tafamidis, a TTR stabilizer, showed in a phase III controlled study its ability to slow stage 1 FAP progression. Other strategies are emerging for TTR-FAP (combination doxycycline-tauroursodeoxycholic acid, small interfering RNA, antisense oligonucleotide, monoclonal antibody antiserum amyloid P component). For light chain neuropathy, intensive chemotherapy may be helpful. SUMMARY: There is better recognition of amyloid neuropathies, and hope for enrolling patients with FAP in future clinical trials testing new antiamyloid drugs.

Amyloid neuropathy mimicking chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Amyloid neuropathy is a rare peripheral neuropathy that classically presents as a progressive sensory neuropathy with prominent autonomic involvement. METHODS: We describe 5 patients with amyloid neuropathy (familial amyloid polyneuropathy or acquired amyloidosis) who were initially mistaken to have chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on history, clinical examination, electrodiagnostic studies, and cerebrospinal fluid (CSF) analysis. RESULTS: The diagnosis of CIDP had been retained on clinical and electrophysiological grounds for all patients, but we observed no improvement after immunomodulatory treatment. Nerve biopsy confirmed amyloid deposits in nerves, and molecular genetic analysis showed a mutation of the transthyretin (V30M) gene for 3 patients; the 2 other patients had acquired amyloidosis. CONCLUSIONS: This report emphasizes the need to look for an alternative diagnosis in CIDP patients who do not respond to treatment and to look carefully for symptoms or signs of autonomic involvement in such patients.

[Original articles on axonal neuropathy in 2010]. / Les actualités sur les polyneuropathies axonales en 2010.

During 2010, 15 articles were published which focused on chronic sensorimotor axonal neuropathy; some will be discussed in this review. Clinical diagnosis from signs and symptoms seems to be excessively variable, often overestimating the incidence of diabetic sensorimotor polyneuropathy. Long-term use of Metformin is associated with malabsorption of vitamin B12. Metformin exposure may be a iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. The neuroprotective role of vitamin E against cisplatinperipheral neurotoxicity has been suggested by a phase III study. Metallosis after hip arthroplasty with a cobalt-chromium alloy prosthesis can cause progressive sensory disturbance, hearing loss and hypothyroidism. The effects of electrical stimulation on neuromuscular recovery after nerve crush injury in rats do not support a benefit of the tested protocol using electrical stimulation during the period of motor nerve recovery following injury. The rate of motor vehicle accidents in patients with neuropathy, based on surveys from 260 subjects, demonstrated that 40.6% were involved in traffic accidents. Accident frequency and discomfort with driving are higher in neuropathy patients compared to age-matched national statistics. Peripheral neuropathy in primary (AL) amyloidosis may be the cause of stepwise progressive, multiple upper limb mononeuropathies.

[New elements in the diagnosis and the treatment of primary AL amyloid polyneuropathy and neuropathy due to POEMS syndrome]. / Nouveautés dans le diagnostic et le traitement des neuropathies périphériques liées à l'amylose AL et au syndrome POEMS.

INTRODUCTION: Primary AL amyloid polyneuropathy (AL-PN) and neuropathy due to POEMS syndrome (POEMS-N) are rare, associated with a monoclonal gammopathy (MG) IgGλ or IgAλ at a low rate and systemic manifestations. They are invalidating and life-threatening. STATE OF THE ART: AL-PN usually mimics small fiber length-dependent axonal polyneuropathies, but also multifocal or painful neuropathies, POEMS-N corresponds to a rapid ascending CIDP with MG. To confirm the diagnosis of AL-PN, initial investigations should identify amyloidosis on nerve or accessory salivary glands, to establish the type of amyloid after serum free light-chain (FLC) measurements. For the diagnosis of N-POEMS, diagnosis is based on the presence of four criteria proposed by Dispenzieri. These neuropathies are associated with biomarkers, useful for diagnosis and treatment monitoring: elevated serum level of FLC monoclonal in (AL-PN) or VEGF (N-POEMS). PERSPECTIVES: Early diagnosis of these neuropathies and early treatment using high-dose melphalan associated with an autologous hematopoietic stem cell graft or low monthly doses can improve the clinical manifestations and patient survival. CONCLUSIONS: Systematic search for monoclonal gammopathy by immunofixation and serum free light chains is very useful for the management of progressive peripheral neuropathies of unknown origin.

Primary AL amyloid polyneuropathy successfully treated with high-dose melphalan followed by autologous stem cell transplantation.

We report 2 patients with polyneuropathy associated with amyloid derived from light chains (AL) who were treated successfully with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT). Neuropathic symptoms improved in conjunction with normalization of serum-free light chains. In addition to amyloid deposits in tissues, an amyloidogenic light chain itself produced by abnormal plasma cells might be harmful to peripheral nerve function, and thus HDM/SCT seems to be a promising therapy for primary AL amyloid polyneuropathy.

Usefulness of combined nerve and muscle biopsy in the diagnosis of amyloid neuropathy--a study of 6 new cases.

OBJECTIVE: Most cases of familial amyloid polyneuropathy are identified by molecular genetic analysis of the transthyretin (TTR) gene. However, it is not uncommon to find unexpected amyloid deposits marked by the anti-TTR serum in the endoneurium of aged patients. Light chain amyloid deposits may also be found in the endoneurium. During these past 5 years, we studied the muscle and nerve biopsies from 6 patients which revealed amyloid deposits. There were 2 patients with an idiopathic polyneuropathy and 4 with monoclonal gammopathy (MG). METHODS: In each case, specimens from the superficial peroneal nerve and peroneus brevis muscle were taken by the same cutaneous incision. RESULTS: Amyloid deposits were visible in the endoneurium of 2 cases and only on muscle specimens in 3 other cases, 1 with a MG and 2 with an idiopathic polyneuropathy. Amyloid deposits were strongly stained with the anti-TTR serum in the muscle specimens of the 2 idiopathic cases, mainly located in vessel walls. In one patient with polyneuropathy and MG, a small endoneurial amyloid deposit surprisingly revealed to be immunostained by the anti-TTR serum. In another case, a small amyloid deposit in close relationship with a macrophage was only visible in the endoneurium by electron microscopy. COMMENTS: Amyloid deposits were only visible on muscle fragments in 3 cases and were strongly marked by the anti-TTR serum in 2 of them, indicating their familial origin. Combining muscle and nerve biopsy raises the number of cases with visible amyloid deposits.

[Myeloma disease with concomitant macroglossia: case report].

The paper describes a patient presenting with myeloma disease with concomitant macroglossia simulating a neoplasm in the bottom of the oral cavity and complicated by laryngeal paresis and the development of grade III stenosis. A brief characteristic of myeloma disease, amyloidosis, and macroglossia syndrome is provided. The authors focus attention on the main diagnostic criteria for this pathology and discuss possible diagnostic mistakes.

[Hereditary and acquired transthyretin-mediated amyloidosis]. / Erfelijke en verworven transthyretine-gemedieerde amyloïdose.

We describe three cases, two 70-year-old males with mainly cardiac symptoms and a 34-year-old male with gastro-intestinal and neurologic symptoms. Each patient was shown to have a distinctive type of transthyretin-mediated amyloidosis (ATTR). ATTR amyloidosis is a life-threatening disease characterised by the extracellular deposition of pathogenic transthyretin (TTR). A distinction is made between hereditary ATTR (ATTRv), in case of a pathogenic TTR mutation, and the acquired wild-type ATTR (ATTRwt). The prevalence of ATTR amyloidosis is probably underestimated. The variety of symptoms means that patients often visit several specialists, resulting in an average diagnostic delay of two to three years. Because of the development of new therapeutic possibilities, early diagnosis becomes more important to allow initiation of therapy at an early stage of the disease. Family members should be screened and asymptomatic carriers should undergo follow-up.

Patient with amyloidoma of the ulnar nerve and salivary glands.

Amyloidomas of the peripheral nervous system have been reported rarely. We describe a patient with a history of localized amyloidosis of the salivary glands who presented a few years later with paresthesias of her left medial arm, forearm, and fifth digit. A mass affecting the left ulnar nerve was confirmed by MRI studies. It was excised and proven on pathological examination to be an amyloidoma. The benign course of this patient's illness is consistent with localized amyloidosis affecting two different organs.