Diagnosis and Screening of Patients with Hereditary Transthyretin Amyloidosis (hATTR): Current Strategies and Guidelines.

The outlook for transthyretin amyloidosis (ATTR) is changing with the availability of new and emerging treatments. ATTR now appears to be more common than previously thought and is no longer viewed as an obscure diagnosis with a grim prognosis. Now more than ever, there is growing emphasis on the need for early diagnosis because the treatments appear to be most effective if started in earlier stages of the disease. Diagnosing ATTR is a challenge as it may initially present with nonspecific symptoms and it is often thought of as a diagnosis of exclusion. Increased awareness is imperative as new treatments offer hope and have the potential to change the disease trajectory. ATTR commonly presents with neurological and cardiac features. Transthyretin (TTR) is a protein produced in the liver which misfolds either due to genetic mutations or due to aging and results in deposition of amyloid fibrils in organs and tissues. Apart from the traditional imaging modalities, newer techniques including echocardiographic strain imaging, magnetic resonance imaging (MRI), and nuclear scintigraphy, as well as the increased availability of genetic testing are aiding in making a timely diagnosis. In this review, we present the current understanding of the ATTR disease process, diagnostic and surveillance approaches, newer treatment modalities, and the future directions.

Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Maternal collapse: Challenging the four-minute rule.

INTRODUCTION: The current approach to, cardiopulmonary resuscitation of pregnant women in the third trimester has been to adhere to the "four-minute rule": If pulses have not returned within 4min of the start of resuscitation, perform a cesarean birth so that birth occurs in the next minute. This investigation sought to re-examine the evidence for the four-minute rule. METHODS: A literature review focused on perimortem cesarean birth was performed using the same key words that were used in formulating the "four-minute rule." Maternal and neonatal injury free survival rates as a function of arrest to birth intervals were determined, as well as actual incision to birth intervals. RESULTS: Both maternal and neonatal injury free survival rates diminished steadily as the time interval from maternal arrest to birth increased. There was no evidence for any specific survival threshold at 4min. Skin incision to birth intervals of 1min occurred in only 10% of women. CONCLUSION: Once a decision to deliver is made, care providers should proceed directly to Cesarean birth during maternal cardiac arrest in the third trimester rather than waiting for 4min for restoration of the maternal pulse. Birth within 1min from the start of the incision is uncommon in these circumstances.

Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials.

Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests.

Amniotic fluid embolism: Then and now.

BACKGROUND: The first case report to describe amniotic fluid embolism that appeared in 1926 in Basil-Medico is translated from Portuguese to English. CASE: A patient with a dead fetus for several weeks, presented in labor and died suddenly with fetal squames evident in the maternal pulmonary vasculature at autopsy. CONCLUSION: As can be seen from the translation, this case report is remarkably similar in many of its features to some of the eight patients described 15 years later in the first English language discussion of the disease by Steiner and Luschbaugh in JAMA. An enigma presented by this first case remains today: fetal material in the maternal pulmonary vasculature appears specific for amniotic fluid embolism at autopsy but not in living patients.

Pulmonary embolism in pregnancy. Consensus and controversies.

Venous thrombotic events (VTE) occur 1-2 per 10,000 pregnancies and remain one of the leading causes of maternal mortality in the developed world. The two largest risk factors are a personal history of VTE and heritable thrombophilias. D-dimer tests for VTE in pregnancy have a high false positive rate and at least some false negatives have been reported. Compression ultrasound should be used to evaluate pregnant women for deep venous thrombosis followed by magnetic resonance imaging of the pelvis for a negative test and strong remaining clinical suspicion. For pulmonary embolism, a chest x-ray should be used to triage the patient to either a ventilation/perfusion study after a normal X-ray or a CT pulmonary angiogram after an abnormal one. Treatment generally consists of low molecular weight heparin through a minimum of six weeks post-partum. Thombolysis might have merit in life-threatening, massive pulmonary embolism. VTE prophylaxis in at-risk populations remains a major area of uncertainty. Mechanical prophylaxis for all women undergoing cesarean, in particular, has a paucity of supportive evidence.

Cardiopulmonary distress during obstetrical anaesthesia: attempts to diagnose amniotic fluid embolism in a case series of suspected allergic anaphylaxis.

BACKGROUND: Cardiopulmonary distress during obstetrical anaesthesia may result from a drug-induced allergic reaction, but, in the obstetrical setting, allergic anaphylaxis may be inseparable from amniotic fluid embolism in terms of the clinical presentation. Further investigations, using allergy tests and other laboratory analyses, are then needed to pursue a diagnostic clarification. METHODS: Twelve women suspected of having developed anaphylaxis during obstetrical anaesthesia underwent allergy follow-up investigations and further serological tests with the amniotic fluid embolism marker sialyl Tn and complement factors (C3 and C4) in an attempt to differentiate amniotic fluid embolism from drug-induced allergic anaphylaxis. RESULTS: The diagnostic programme revealed one case of probable amniotic fluid embolism and four cases of probable drug-induced allergic anaphylaxis. Of the remaining seven cases, there were two cases that, by diagnostic exclusion, could be classified as possible cases of amniotic fluid embolism. The cause of the reactions remained unresolved in five cases. CONCLUSIONS: It can be difficult to differentiate between anaphylaxis and amniotic fluid embolism, especially amongst survivors. Diagnostic markers that can be applied on peripheral blood samples are promising, but larger studies are needed to validate their use in the diagnosis of causes of cardiopulmonary distress during obstetrical anaesthesia.

Diaphragmatic paralysis: the use of M mode ultrasound for diagnosis in adults.

STUDY DESIGN: Retrospective, case series. OBJECTIVES: To evaluate the use of M mode ultrasonography in the evaluation of diaphragmatic paralysis in adults. SETTING: Radiology department, Princess Alexandra Hospital, Brisbane, Australia. METHODS: Ten patients who were referred for evaluation of suspected diaphragmatic paralysis were evaluated using M mode ultrasound. RESULTS: Three of the patients who were scanned demonstrated normal diaphragmatic movement. The M mode trace demonstrated normal movement of the diaphragm bilaterally with quiet respiration and a sharp upstroke on the sniff test (indicating normal caudal movement of the diaphragm). Six patients were found to have a unilateral diaphragmatic paralysis. Four of these patients were noted to have a raised hemi-diaphragm on chest radiography. Of the two who did not have a raised hemi-diaphragm on chest radiography, one was permanently ventilated. The M mode trace of the paralyzed side showed no active caudal movement of the diaphragm with inspiration and abnormal paradoxical movement (ie cranial movement on inspiration) particularly with the sniff test. CONCLUSION: M mode ultrasonography is a relatively simple and accurate test for diagnosing paralysis of the diaphragm, in the adult population. It can be performed, if necessary, at the bedside and can be easily repeated if paralysis is not thought to be permanent. EQUIPMENT: Philips ATL Sono CT 5000 using a 2-5 MHz curved linear transducer.

Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene.

Abnormal accumulation of ferritin was found to be associated with an autosomal dominant slowly progressing neurodegenerative disease clinically characterized by tremor, cerebellar ataxia, parkinsonism and pyramidal signs, behavioral disturbances, and cognitive decline. These symptoms may appear sequentially over a period of 4 decades. Pathologically, intranuclear and intracytoplasmic bodies were found in glia and subsets of neurons in the central nervous system as well as in extraneural tissue. Biochemical analyses of these bodies isolated from the striatum and cerebellar cortex revealed that ferritin light polypeptide (FTL) and ferritin heavy polypeptide (FTH1) were the main constituents. Molecular genetic studies revealed a 2-bp insertion mutation in exon 4 of the FTL gene. The resulting mutant polypeptide is predicted to have a carboxy terminus that is altered in amino-acid sequence and length. In tissue sections, the bodies were immunolabeled by anti-ferritin and anti-ubiquitin antibodies and were stained by Perls' method for ferric iron. Synthetic peptides homologous to the altered and wild-type carboxy termini were used to raise polyclonal antibodies. These novel antibodies as well as an antibody recognizing FTH1 immunolabeled the bodies. This study of this disorder has provided additional knowledge and insights in the growing area of ferritin-related neurodegeneration.

Amyloidoma of a spinal root.

A unique case of amyloidoma presenting as a dumbbell-shaped tumor of a spinal root without bony erosion is described. Amyloid was also present in the facial nerve. DNA analysis for transthyretin was negative. Isolated amyloid fibers contained lambda light chains, and although plasma and urine immunoelectrophoresis performed by immunofixation was normal, it is possible the tumor may have been derived from an isolated plasmacytoma.

Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His.

OBJECTIVE: To describe the clinical, radiologic, and pathologic findings of a kindred with oculoleptomeningeal amyloidosis and a newly associated transthyretin mutation. BACKGROUND: Transthyretin (TTR) amyloidosis can present in the form of oculoleptomeningeal amyloidosis. Clinical features include dementia, seizures, stroke-like episodes, subarachnoid hemorrhage, ataxia, myelopathy, deafness, radiculopathy, and ocular amyloidosis. Eight TTR mutations associated with oculoleptomeningeal amyloidosis have been described. METHODS: Fourteen individuals from a kindred with oculoleptomeningeal amyloidosis were examined clinically and radiologically. Analysis of the TTR gene was performed. Neuropathologic examination was obtained on the index patient. RESULTS: Affected individuals had vitreous amyloid, radiculopathy, seizures, stroke-like episodes, encephalopathy, and dementia. Severely affected individuals died by the end of the fifth decade. Leptomeningeal enhancement on contrast MRI and elevated CSF protein were the defining features on investigations. Sequencing of exon 3 in the TTR gene found a base pair substitution at codon 69. This resulted in heterozygosity for normal tyrosine and variant histidine (ATTR Tyr69His) in affected family members. Domino liver transplantation was attempted as treatment for one family member. CONCLUSIONS: The ATTR Tyr69His mutation is associated with oculoleptomeningeal amyloidosis. Expression of the genotype is variable. This has implications for treatment of affected individuals and counseling of family members. Efficacy of liver transplantation in patients with oculoleptomeningeal amyloidosis remains unknown. The authors advocate the investigation of liver transplantation in patients with severe symptoms due to oculoleptomeningeal amyloidosis.

Transthyretin: a review from a structural perspective.

Transthyretin (formerly called prealbumin) plays important physiological roles as a transporter of thyroxine and retinol-binding protein. X-ray structural studies have provided information on the active conformation of the protein and the site of binding of both ligands. Transthyretin is also one of the precursor proteins commonly found in amyloid deposits. Both wild-type and single-amino-acid-substituted variants have been identified in amyloid deposits, the variants being more amyloidogenic. Sequencing of the gene and the resulting production of a transgenic mouse model have resulted in progress toward solving the mechanism of amyloid formation and detecting the variant gene in individuals at risk.