Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis.

INTRODUCTION: Hereditary transthyretin-mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO-TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. METHODS: Stage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks. RESULTS: At 66 weeks, inotersen-treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items. DISCUSSION: Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients' neuropathy experience in clinical practice.

mNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis.

INTRODUCTION: Inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR-mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test. METHODS: Adults with hATTR in the NEURO-TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks. RESULTS: All major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS-reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects. DISCUSSION: The results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

The role of next generation sequencing in infection prevention in human parainfluenza virus 3 infections in immunocompromised patients.

BACKGROUND: Respiratory viral infections are a significant problem in patients with hematologic malignancies. We report a cluster of HPIV 3 infections in our myeloma patients, and describe the utility of next generation sequencing (NGS) to identify transmission linkages which can assist in infection prevention. OBJECTIVES: To evaluate the utility of NGS to track respiratory viral infection outbreaks and delineate between community acquired and nosocomial infections in our cancer units. STUDY DESIGN: Retrospective chart review conducted at a single site. All patients diagnosed with multiple myeloma who developed symptoms suggestive of upper respiratory tract infection (URTI) or lower respiratory tract infection (LRTI) along with a respiratory viral panel (RVP) test positive for HPIV 3 between April 1, 2016, to June 30, 2016, were included. Sequencing was performed on the Illumina MiSeq™. To gain understanding regarding community strains of HPIV 3 during the same season, we also performed NGS on HPIV3 strains isolated from pediatric cases. RESULTS: We saw a cluster of 13 cases of HPIV3 infections in the myeloma unit. Using standard epidemiologic criteria, 3 cases were considered community acquired, 7 cases developed infection during treatment in the cancer infusion center, while an additional 3 developed infections during hospital stay. Seven patients required hospitalization for a median duration of 20days. NGS enabled sensitive discrimination of the relatedness of the isolates obtained during the outbreak and provided evidence for source of transmission. Two hospital onset infections could be tracked to an index case; the genome sequences of HPIV 3 strains from these 3 patients only differed by a single nucleotide. CONCLUSIONS: NGS offers a significantly higher discriminatory value as an epidemiologic tool, and can be used to gather real-time information and identification of transmission linkages to assist in infection prevention in immunocompromised patients.

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial.

INTRODUCTION: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. METHODS: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. RESULTS: The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. CONCLUSIONS: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Rate of progression of transthyretin amyloidosis.

Hereditary transthyretin (TTR) amyloidosis is an adult-onset disease characterized mainly by peripheral neuropathy and cardiomyopathy. Although disease progression is usually 5 to 15 years from time of diagnosis to death, no specific measurements of disease progression have been identified. The present study was designed to identify objective parameters to measure progression of hereditary TTR amyloidosis and determine if these parameters would show significant change within 1 year. Nine patients with biopsy-proved TTR amyloidosis and evidence of cardiac involvement were studied at baseline, 6 months, and 12 months by cardiac magnetic resonance imaging (MRI), electrocardiogram, and echocardiogram. Neurologic impairment score and electromyogram were determined at baseline and 12 months. Left ventricular mass determined by MRI and echocardiogram showed significant change at 12-month examination (p = 0.005 and p = 0.0009, respectively). Electrocardiogram and neurologic impairment score did not show significant change at 12 months. Measurement of left ventricular mass by MRI and echocardiographic techniques showed significant change in hereditary TTR cardiac amyloidosis within 1 year. In conclusion, these methods provide a means to clinically monitor progression of hereditary TTR amyloidosis and determine efficacy of therapeutic interventions.

Local neurotoxins for prevention of laryngeal synkinesis after recurrent laryngeal nerve injury.

OBJECTIVES: Persistent vocal fold motion impairment after recurrent laryngeal nerve (RLN) injury is not characteristically due to absent reinnervation, but often results from spontaneous aberrant reinnervation (synkinesis). We administered local neurotoxins to selected laryngeal muscles after RLN injury to determine whether aberrant reinnervation could be selectively inhibited. METHODS: Unilateral RLN transection was performed in 24 male rats. Three weeks later, the denervated laryngeal adductor complex was injected with phenol, high- or low-dose vincristine sulfate (VNC), or saline solution. One month later, rat larynges were evaluated via videolaryngoscopy and laryngeal electromyography (LEMG). Larynges from euthanized animals were analyzed via immunofluorescent staining for the presence of reinnervation. RESULTS: One animal that received phenol and 3 animals that received high-dose VNC died of toxicity-related complications. In the surviving neurotoxin-treated animals, videolaryngoscopy showed increased lateralization of the immobile vocal fold. Only 1 phenol-injected rat had adductor complex motor recruitment (score of 3+) with LEMG. The other neurotoxin-treated animals demonstrated an absence of adductor complex reinnervation, with only insertional activity and fibrillations (no motor units/recruitment). Spontaneous ipsilateral abductor reinnervation was not affected by the adductor injections. CONCLUSIONS: Low-dose VNC injections appear to be relatively safe and effective in selectively inhibiting spontaneous aberrant reinnervation after RLN injury in an animal model.

The molecular biology and clinical features of amyloid neuropathy.

Neuropathy is often a major manifestation of systemic amyloidosis. It is most frequently seen in patients with hereditary transthyretin (TTR) amyloidosis, but is also present in 20% of patients with systemic immunoglobulin light chain (primary) amyloidosis. Familial amyloid polyneuropathy (FAP) is the most common form of inherited amyloidotic polyneuropathy, with clinical and electrophysiologic findings similar to neuropathies with differing etiologies (e.g., diabetes mellitus). Hereditary amyloidosis is an adult-onset autosomal-dominant disease with varying degrees of penetrance. It is caused by specific gene mutations, but demonstration that a patient has one such mutation does not confirm the diagnosis of amyloidosis. Diagnosis requires tissue biopsy with demonstration of amyloid deposits either by special histochemical stains or electron microscopy. Transthyretin amyloidosis is treated by liver transplantation, which eliminates the mutated transthyretin from the blood, but for some patients continued amyloid deposition can occur from wild-type (normal) transthyretin. Presently, a study is ongoing to determine whether amyloid deposition can be inhibited by small organic molecules that are hypothesized to affect the fibril-forming ability of transthyretin. Proposed gene therapy with antisense oligonucleotides (ASOs) to suppress hepatic transthyretin synthesis is effective in a transgenic mouse model but has not yet been tested in humans.

Contribution of wild-type transthyretin to hereditary peripheral nerve amyloid.

To elucidate the contribution of wild-type transthyretin (TTR) to amyloid polyneuropathy in TTR amyloidosis, we biochemically investigated amyloid fibrils isolated from sciatic nerve of an autopsied patient with TTR Ala25Ser variant and compared the amount of wild-type and variant TTR in the nerve to that in the heart. Amyloid subunit protein from isolated fibrils was solubilized in 6M guanidine HCl and purified by gel filtration chromatography. The relative amounts of variant and wild-type TTR in the purified protein were estimated from the recovered amounts of tryptic peptides with Ser25 or Ala25. Approximately 60% variant and 40% wild-type TTR were found in both the nerve and heart amyloid deposits. Our results indicate that wild-type TTR co-deposits in the peripheral nerves with variant TTR as amyloid fibril, and therefore that progression of amyloid deposition in the peripheral nerves from wild-type TTR may occur after liver transplantation, as has been seen in the heart.

Rapidly progressive amyloid polyneuropathy associated with a novel variant transthyretin serine 25.

We report a 52-year-old woman with a novel transthyretin (TTR) variant serine replacing alanine at residue 25 [Ala25Ser (Serine 25)], who showed a unique clinical picture with a relatively acute onset neuropathy within a few days of an influenza vaccination, progressing to a severe degree within 2 years. Sural nerve biopsy revealed amyloid deposition in the endoneurium. Sequencing of the proband's DNA revealed a G to T transversion at the first position of codon 25 of TTR gene. DNA analysis of this family showed the same mutation in her older sister and a niece, but her parents did not have the mutation. Haplotype analysis revealed the mutation to be clearly linked to haplotype III allele inherited from the proband's father. These results indicate this novel Serine 25 mutation originated in the paternal germline mosaicism. It is possible that the vaccination had an influence on the unique clinical picture, but this remains uncertain.