Neuromuscular Complications of Systemic Amyloidosis.

Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues, frequently at a distance from the site of synthesis. The 2 most common forms, light chain (AL) and transthyretin (ATTR) amyloidosis can cause peripheral neuropathy and, rarely, myopathy. Diagnosis can be challenging, and abundant suspicion is required to identify patients. As neurological manifestations of amyloidosis may precede involvement of other organs by several years, recognizing amyloid neuropathy and myopathy are crucial, especially in this new and exciting era of effective therapies for AL and ATTR neuropathy. This review will focus on the neuromuscular manifestations of AL and ATTR amyloidosis, diagnostic approaches, and recent advances in the treatment of amyloid neuropathy.

Demyelinating Neuropathy in a Patient Treated With Revusiran for Transthyretin (Thr60Ala) Amyloidosis.

Transthyretin amyloidosis patients develop length-dependent peripheral neuropathy, autonomic dysfunction, and restrictive cardiomyopathy associated with deposition of amyloid fibrils in these tissues. Despite advances in management over the past decade, this disorder causes profound debilitation and ultimately proves fatal. In this report, we describe a man with late-onset cardiac amyloidosis due to a transthyretin Thr60Ala mutation who was treated with an investigational RNAi therapeutic, revusiran, which targets hepatic transthyretin production. Sixteen months into treatment, he developed bilateral lower-extremity weakness and numbness, worsening balance, difficulty manipulating objects with his hands, and finger numbness. Nerve conduction studies were consistent with multifocal demyelinating neuropathy. Intravenous immunoglobulin therapy improved sensation in his hands and feet, and improved hand dexterity. A sural nerve biopsy demonstrated demyelination with substantial axonal loss in the absence of histologically detectable endoneurial amyloid deposition. This case expands the clinicopathologic spectrum of transthyretin amyloidosis and may represent complex disease and treatment effects.

Amyloidosis of the Breast: Three Different and Unusual Presentations of a Rare Entity.

BACKGROUND: Amyloidosis involving the breast is a rare finding and it may present as a solitary mass called 'amyloid tumor'. According to the largest case series, the amyloid deposits are usually of the AL type (commonly x03BA; light chain). METHODS: We report 3 cases diagnosed at our institution in the period from 2000 to 2015. Radiological, histological and immunohistochemical studies were performed. RESULTS AND CONCLUSIONS: Together with a case presenting in a patient with multiple myeloma, we describe 2 unique presentations including 1 associated with CREST syndrome in a patient with a previous history of breast carcinoma and another, also associated with cancer, with transthyretin deposits in a woman with a TTR gene mutation and a family history of familial amyloidotic polyneuropathy. These cases are an example of the vast heterogeneity of this disorder regarding its clinical presentation, the type of amyloid deposits and other diseases associated with breast amyloidosis.

Light-chain cardiac amyloidosis with neuropathy: a case report.

Light-chain amyloidosis is a relatively rare multisystem disorder. The disease often is normally difficult to diagnose due to its broad range of characters without specific symptoms. A 62-year-old male patient presented with heart failure after experiencing a long period of unexplained and untreated gastrointestinal symptoms. Clinical examination and laboratory findings indicated a systemic process with cardiac involvement. Echocardiography revealed concentric left ventricular hypertrophy with enhanced echogenicity and preserved ejection fraction. Rectum biopsy confirmed amyloid deposition. The side effect of delayed diagnosis on prognosis and the appropriate diagnostic strategy has been discussed.

Teaching neuroimages: dyspnea as a presenting manifestation of amyloid myopathy.

A 69-year-old man had dyspnea followed by slowly progressive proximal leg weakness over 2 years. He had macroglossia (figure 1). Creatine kinase was 1,378 U/L. A deltoid biopsy revealed myopathy, denervation atrophy, and congophilic deposits around perimysial vessels, indicating amyloid (figure 2). Further workup revealed serum monoclonal lambda protein, bone marrow amyloid, and cardiomyopathy. Amyloid myopathy, an underrecognized entity, predominantly presents with progressive proximal weakness in primary amyloidosis.(1) Dyspnea results from cardiomyopathy or respiratory muscle weakness (our patient had both). Macroglossia due to amyloid deposition is a helpful clinical clue. The patient is on chemotherapy with cyclophosphamide, dexamethasone, and bortezomib, which improves prognosis in amyloidosis.(2.)

In vivo and in vitro effects of an apolipoprotein e mimetic peptide on amyloid-ß pathology.

BACKGROUND: Apolipoprotein E (ApoE) is the major apolipoprotein present in the high-density lipoprotein-like particles in the central nervous system (CNS). ApoE is involved in various protective functions in CNS including cholesterol transport, anti-inflammatory, and antioxidant effects. An ApoE peptide would be expected to exert protective effects on neuroinflammation. OBJECTIVE: To determine the effects of an ApoE mimetic peptide Ac-hE18A-NH2 on amyloid-ß pathology. METHOD: Using human APP/PS1ΔE9 transgenic mice and in vitro studies, we have evaluated the effect of an ApoE mimetic peptide, Ac-hE18A-NH2, on amyloid plaque deposition and inflammation. RESULTS: Administration of Ac-hE18A-NH2 to APP/PS1ΔE9 mice for 6 weeks (50 µg/mouse, 3 times a week) significantly improved cognition with a concomitant decrease in amyloid plaque deposition and reduced activated microglia and astrocytes, and increased brain ApoE levels. Oligomeric Aß42 (oAß42) and oxidized PAPC (ox-PAPC) inhibited secretion of ApoE in U251 cells, a human astrocyte cell line, and this effect was ameliorated in the presence of peptide Ac-hE18A-NH2. The peptide also increased Aß42 uptake in a cell line of human macrophages. CONCLUSIONS: Peptide Ac-hE18A-NH2 attenuates the effects of oxidative stress on ApoE secretion, inhibits amyloid plaque deposition, and thus could be beneficial in the treatment of Alzheimer's disease.

Autonomic dysfunction affects cerebral neurovascular coupling.

OBJECTIVE: Autonomic failure (AF) affects the peripheral vascular system, but little is known about its influence on cerebrovascular regulation. Patients with familial amyloidotic polyneuropathy (FAP) were studied as a model for AF. METHODS: Ten mild (FAPm), 10 severe (FAPs) autonomic dysfunction FAP patients, and 15 healthy controls were monitored in supine and sitting positions for arterial blood pressure (ABP) and heart rate (HR) with arterial volume clamping, and for blood flow velocity (BFV) in posterior (PCA) and contralateral middle cerebral arteries (MCA) with transcranial Doppler. Analysis included resting BFV, cerebrovascular resistance parameters (cerebrovascular resistance index, CVRi; resistance area product, RAP; and critical closing pressure, CrCP), and neurovascular coupling through visually evoked BFV responses in PCA (gain, rate time, attenuation, and natural frequency). RESULTS: In non-stimulation conditions, in each position, there were no significant differences between the groups, regarding HR, BP, resting BFV, and vascular resistance parameters. Sitting ABP was higher than in supine in the three groups, although only significantly in controls. Mean BFV was lower in sitting in all the groups, lacking statistical significance only in FAPs PCA. CVRi and CrCP increased with sitting in all the groups, while RAP increased in controls but decreased in FAPm and FAPs. In visual stimulation conditions, FAPs comparing to controls had a significant decrease of natural frequency, in supine and sitting, and of rate time and gain in sitting position. INTERPRETATION: These results demonstrate that cerebrovascular regulation is affected in FAP subjects with AF, and that it worsens with orthostasis.

Amyloid ß accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double-transgenic mouse model.

In Alzheimer's disease, Aß deposits are considered the initial cardinal events that induce tauopathy secondarily. However, the relationship between Aß amyloidosis and tauopathy has not been determined in detail. We produced double transgenic mice, 2×TgTau(+/-) APP(+/-) , by mating Tg2576 mice that exhibit Aß amyloidosis and TgTauP301L mice that show tauopathy, and statistically analyzed the effect of Aß accumulation on tauopathy. There was no significant difference in theprogression of Aß accumulation among 2×TgTau(+/-) APP(+/-) and 1×TgTau(-/-) APP(+/-) , and tau accumulation among 2×TgTau(+/-) APP(+/-) and 1×Tg Tau(+/-) APP(-/-) . The appearance rates of phosphorylated tau developing in neurons and processes were significantly accelerated in 2×TgTau(+/-) APP(+/-) mice compared with those in 1×TgTau(+/-) APP(-/-) mice at 23 months of age. Accumulation of phosphorylated and confomationally altered tau and GSK3ß in neuronal processes was accelerated in the white matter in 2×TgTau(+/-) APP(+/-) . The level of phosphorylated tau in the sarkosyl-insoluble fraction was increased in 2×TgTau(+/-) APP(+/-) brains compared with that in 1×TgTau(+/-) APP(-/-) brains. Thus, Aß amyloid partially enhances tauopathy through accumulation of insoluble, phosphorylated, and conformationally changed tau in neuronal cytoplasm and processes in the late stage.

[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.

[Left ventricular noncompaction concurrent with bronchoectatic disease complicated by secondary AA-amyloidosis with renal involvement].

The paper describes a clinical case of congenital cardiomyopathy (left ventricular noncompaction) concurrent with secondary amyloidosis and renal involvement that develops at the outcome of long existing brochoectatic disease.

[Amyloid neuropathy resulting from an unknown protein]. / Neuropathie amyloïde liée à une protéine non identifiée.

Amyloid neuropathy is related to acquired or hereditary forms of amyloidosis resulting from transthyretin variants. We reported a 42-year-old man suffering from a peripheral neuropathy not related to transthyretin mutations. Mass spectrometry may be useful to identify this rare form of amyloid neuropathy.

Severe ataxia with neuropathy in hereditary gelsolin amyloidosis: a case report.

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder caused by a G654A or G654T gelsolin mutation, reported from Europe, North America, and Japan. Principal clinical signs are corneal lattice dystrophy, cutis laxa and cranial neuropathy, often deleterious at advanced age. Peripheral neuropathy, if present, is usually mild. We report a 78-year-old male Finnish patient who presented with ataxia and mainly sensory peripheral polyneuropathy (PNP) signs, causing severe disability and ambulation loss. Electrophysiological studies showed severe generalized chronic mainly axonal sensorimotor PNP with facial paralysis. In magnetic resonance imaging proximal lower limb and axial muscle atrophy with fatty degeneration as well as moderate spinal cord atrophy were seen. A G654A gelsolin mutation was demonstrated but no other possible causes of his disability were found. At age 79 years he became bedridden and died of pulmonary embolism. Neuropathological examination revealed marked gelsolin amyloid deposition at vascular and connective tissue sites along the entire length of the peripheral nerves extending to the spinal nerve roots, associated with severe degeneration of nerve fibers and posterior columns. Our report shows that advanced AGel amyloidosis due to degeneration of central and distal sensory nerve projections results in deleterious ataxia with fatal outcome. Severe posterior column atrophy may reflect radicular AGel deposition, although even altered gelsolin-actin interactions in neural cells possibly contribute to neurodegeneration with successive ataxia in carriers of a G654A gelsolin mutation.

Quantified sensory abnormalities in early genetically verified transthyretin amyloid polyneuropathy.

Transthyretin amyloid neuropathy of type 1 (Swedish-Portuguese type) is an autosomally inherited progressive disease with a Val30Met mutation, causing generalized sensory-motor polyneuropathy. Quantitative sensory testing (QST) quantifies thermal threshold changes in patients with manifest general polyneuropathy, but its applicability at an early clinical stage of a strict biochemically defined disease has not yet been shown. Thermal QST was performed in 23 patients having a positive Val30Met marker and clinical symptoms of peripheral small-fiber neuropathy but normal electrophysiological findings and compared to a reference group of 43 healthy volunteers, both subdivided into age groups < or =45 and >45 years. Significant differences between patients and controls were found at all test sites in both age groups, except for warm thresholds at the medial lower leg in those >45 years. QST thus demonstrated elevated thermal thresholds before the development of electrophysiological abnormalities, which indicate large-fiber involvement. These findings confirm that QST is a useful method for documentation of developing polyneuropathy.

Isolated amyloidosis presenting with lumbosacral radiculoplexopathy: description of two cases and pathogenic review.

In this study, we present two cases of infiltrative, localized amyloidosis involving lumbosacral root and plexus, e.g., isolated amyloidomas. Rare and poorly understood amyloidomas may occur in both neurologic and non-neurologic tissues. The described cases emphasize potential for localized peripheral amyloidomas: (1) potential for associated lambda light chain lymphoplasmacytic lymphoma association; (2) e isolated amyloidosis without evidence for systemic plasma cell dyscrasia; (3) features suggestive of potential pathogenesis; and (4) discussion of treatment options including immunotherapy and resection. The limited literature and experience among other cases is described.

Bilateral carpal tunnel syndrome associated to familial Mediterranean fever.

A unique case of bilateral severe carpal tunnel syndrome due to familial Mediterranean fever is reported. The syndrome was diagnosed by clinical examination and electrophysiological studies. Bilateral transverse carpal ligaments were released and the biopsy specimens revealed systemic type A amyloidosis. Up to our knowledge, the co-existence of bilateral carpal tunnel syndrome and familial Mediterranean fever has not been reported previously in the literature.

Collapse in a 79-year-old: a rare case of amyloid tumour of the pelvis.

A 79-year-old man presented to accident and emergency with collapse, unable to bear weight on his left leg. Computed tomography revealed a large isolated lesion (28 x 12 x 8 cm) extending from the pelvis into the abdomen, affecting the left lumbrosacral nerves. Further investigations showed that the mass contained amyloid protein. With no evidence of systemic amyloidosis or malignancy a diagnosis of amyloidoma/amyloid tumour was made. This is the largest amyloid tumour reported in the literature to date. There is limited but conflicting evidence regarding the pathophysiology, management and prognosis of amyloidoma. Clearly amyloidomas are rare, but patients can present acutely and may have a poor prognosis, especially when the tumour is of considerable size.

Distrofia simpático refleja asociada al tratamiento con tacrolimus / Reflex sympathetic dystrophy associated to treatment with tacrolimus

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Polineuropatía y miopatía del paciente crítico: ¿en qué hemos avanzado? / Polyneuropathy and myopathy in the critically ill. Where have we made progress?

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