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.

Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.

Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients, respectively, beginning at an average age of 43, 41, and 56 years, respectively. Approximately 9% of patients with VCP mutations had an amyotrophic lateral sclerosis (ALS) phenotype, 4% had been diagnosed with Parkinson's disease (PD), and 2% had been diagnosed with Alzheimer's disease (AD). Large interfamilial and intrafamilial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared with other molecular subtypes.

[Craniosynostosis and strabismus].

Craniosynostosis(CS), the premature fusion of cranial sutures leading to an abnormal shape and precocious maturity of skull, is classified into Non-syndromic Craniosynostosis (NSC) and Syndromic Craniosynostoses(SC).NCS only has different abnormality of skull according to which cranial suture is involved while extra malformation of midface and limbs present in SCS. Common SCS contains Crouzon Syndrome, Apert Syndrome, Pfeiffer Sydrome, and etc. The clinical manifestation of CS includes malformation of skull, intracranial hypertension, brain hernia, developmental disorder of cerebral function, strabismus, and etc, while SCS has more complex manifestation. Along with the improvement of multidisciplinary cooperation, the ophthalmic complication of CS, like strabismus, is recognised by oculists gradually. This review is summarizing the clinical manifestation, complicated strabismus, pathogenesis and multidisciplinary cure of CS. (Chin J Ophthalmol, 2016, 52: 626-630).

Effect of trapped energetic particles on the resistive wall mode.

A stability analysis for the resistive wall mode is studied in the presence of trapped energetic particles (EPs). When the EPs' beta exceeds a critical value, a fishbonelike bursting mode (FLM) with an external kink eigenstructure can exist. This offers the first analytic interpretation of the experimental observations [Phys. Rev. Lett. 103, 045001 (2009)]. The mode-particle resonances for the FLM and the q=1 fishbone occur in different regimes of the precession frequency of EPs. In certain ranges of the plasma rotation speed and the EPs' beta, a mode conversion can occur between the resistive wall mode and FLM.

Botulinum toxin type A in primary palmar hyperhidrosis: randomized, single-blind, two-dose study.

BACKGROUND: Primary palmar hyperhidrosis is characterized by excessive sweating due to increased sympathetic cholinergic sudomotor nerve traffic to the palmar surface of the hands. Clinical studies suggest that intradermal injections of botulinum toxin are effective in the treatment of palmar hyperhidrosis. OBJECTIVES: To establish the effectiveness of intradermal botulinum toxin in reducing hyperhidrosis, to determine the most effective dose of toxin, and to examine its effect on muscle strength. METHODS: In a prospective, single blind, randomized trial, 24 patients with severe palmar hyperhidrosis received either a low (50 U) or a high dose (100 U) of botulinum toxin type A (Botox, Allergan) injected intradermally in 20 sites in each palm. RESULTS: Following injection with either dose, iodine starch test revealed a significant decrease in sweating within the first month. Six months after injection, the anhidrotic effect was still evident in two thirds of the patients in both groups. Handgrip strength was not affected with either dose but finger pinch strength, 2 weeks after the injection, decreased 23 +/- 27% with 50 U (p < 0.05) and 40 +/- 21% with 100 U (p < 0.001). Pinch strength improved gradually but 6 months after treatment it was still 7-11% lower than at baseline. CONCLUSIONS: Both 50 and 100 U of botulinum toxin type A, injected intradermally in each hand, decreased sweating in patients with primary hyperhidrosis for at least 2 months in all the patients, and 6 months in most patients. Weakness in the intrinsic muscles of the hand was observed.

HIV-associated peripheral neuropathy: epidemiology, pathophysiology and treatment.

Peripheral neuropathy is the most frequent neurological complication associated with human immunodeficiency virus type 1 (HIV) infection and advanced acquired immunodeficiency syndrome (AIDS). There are at least 6 patterns of HIV-associated peripheral neuropathy, although these diagnoses are often overlooked or misdiagnosed. Distal symmetrical polyneuropathy (DSP) is the most common form of peripheral neuropathy in HIV infection. DSP occurs mainly in patients with advanced immunosuppression and may also be secondary to the neurotoxicity of several antiretroviral agents. Treatment of painful DSP is primarily symptomatic, while pathogenesis-based therapies are under investigation. Reduction or discontinuation of neurotoxic agents should be considered if possible. Inflammatory demyelinating polyneuropathy (IDP) can present in an acute or chronic form. The acute form may occur at the time of primary HIV infection or seroconversion. Cerebrospinal fluid lymphocytic pleocytosis (10 to 50 cells/mm3) is helpful in the diagnosis of HIV-associated IDP. Treatment consists of immunomodulatory therapy. Progressive polyradiculopathy (PP) most commonly occurs in advanced immunosuppression and usually is caused by cytomegalovirus (CMV) infection. Rapidly progressive flaccid paraparesis, radiating pain and paresthesias, areflexia and sphincter dysfunction are the cardinal clinical features. Rapid diagnosis and treatment with anti-CMV therapy are necessary to prevent irreversible neurological deficits resulting from nerve root necrosis. Mononeuropathy multiplex (MM) that occurs in early HIV infection is characterised by self-limited sensory and motor deficits in the distribution of individual peripheral nerves. In advanced HIV infection, multiple nerves in two or more extremities or cranial nerves are affected. Treatment includes immunomodulation or anti-CMV therapy. Autonomic neuropathy may be caused by central or peripheral nervous system abnormalities. Treatment is supportive with correction of metabolic or toxic causes. Diffuse infiltrative lymphocytosis syndrome (DILS) presents as a Sjögren's-like disorder with CD8 T cell infiltration of multiple organs. Antiretroviral therapy and steroids may be effective treatments.

Effect of simple analgesics on quantitative sensation test threshold.

Twenty individuals underwent quantitative sensation testing (QST) before and after 1 dose of aspirin, acetaminophen, or acetaminophen with codeine to determine the effect of analgesics on QST results. There was no significant change from baseline when mean QST results after placebo were compared to mean QST results after analgesics. We conclude that the effect of small doses of simple analgesics on QST results is either not present or is too small to necessitate withholding analgesics before sensory testing.

Heat sensitivity of sensory fibers in carpal tunnel syndrome.

Elevations in temperature may produce conduction block in demyelinated neurons. A well-described phenomenon in multiple sclerosis, it has also been reported in some patients with inflammatory demyelinating polyneuropathies. We used carpal tunnel syndrome (CTS) as a model to study the effect of heat on nerves with focal demyelination secondary to chronic compression. Compound motor and sensory responses were measured in 12 CTS patients and 12 normal subjects at 32 degrees C and with heating to 42 degrees C. Changes in relative motor response amplitude and area were similar for both normal subjects and CTS patients. In CTS patients, however, sensory response amplitude and area decreased 34.3% and 48.9%, significantly more than the 25.2% and 39.1% reductions in normal subjects (P=0.021 and P=0.018 respectively). We hypothesize that these reductions in response amplitude are secondary to the occurrence of heat-induced conduction block in demyelinated sensory neurons.

High-temperature repetitive nerve stimulation in myasthenia gravis.

High temperature enhances the decrement on repetitive nerve stimulation (RNS) in patients with myasthenia gravis (MG). However, the limit of this phenomenon at high temperature is unknown. Three-hertz ulnar RNS was performed in 7 patients with MG at a skin temperature of 32 degrees C and then with the hand in a 44 degrees C water bath. At 32 degrees C, the mean decrement preactivation was 5% (range, 0-24%); after 1 min of exercise, the mean decrement reached a maximum of 11% (range, 1-34%) 2 min postactivation. At a hand temperature of 42 degrees C, the mean decrement preactivation was 17% (range, 0-65%); after exercise, the mean decrement reached a maximum of 29% (range, 5-74%) 1 min postactivation. In 3 subjects, RNS was normal at 32 degrees C, but a definite decrement developed with heating. These findings demonstrate that very high temperature can improve the sensitivity of ulnar RNS for postsynaptic neuromuscular transmission defects.

Neuroimaging findings in patients on immunosuppressive therapy: experience with tacrolimus toxicity.

OBJECTIVE: The purpose of this study is to describe the neuroimaging (CT and MR imaging) findings in liver transplant patients who develop severe neurologic side effects during immunosuppressive therapy with tacrolimus and to correlate these findings with clinical signs and tacrolimus levels in blood. SUBJECTS AND METHODS: Brain CT and/or MR imaging was performed on six patients who developed neurologic symptoms while receiving tacrolimus in the post-transplant period. All patients were evaluated by the neurology staff, and imaging studies were independently interpreted by three neuroradiologists. Trough tacrolimus levels in blood were measured with the IMX immunoassay and were correlated with neurologic symptoms and imaging findings. RESULTS: Imaging abnormalities were observed in five of six patients during the course of their neurologic illnesses. For each patient, neurologic symptoms began when the tacrolimus level in blood was at a peak, exceeding the therapeutic limit in all but one case. In five patients, neurologic symptoms eventually resolved after the tacrolimus dose was reduced or after the drug was stopped. Multifocal low attenuation of white matter was the predominant finding seen on CT images, and matching hyperintense white matter foci were observed on long-TR MR images. In three patients, clinical recovery was accompanied by reversal of the white matter abnormalities seen on CT and MR images. CONCLUSION: Immunosuppressive therapy with tacrolimus may produce neurologic side effects that are associated with brain CT and MR imaging abnormalities. Resolution of symptoms and reversal of imaging findings occur when the tacrolimus dose is reduced.

MR imaging of spinal cord and vertebral body infarction.

PURPOSE: To study the usefulness of MR in the evaluation of spinal cord infarctions and associated findings. MATERIALS AND METHODS: MR examinations of 12 patients (10 men and two women) were reviewed retrospectively. Onset of symptoms of spinal cord ischemia was abrupt in all patients; MR was performed 8 hr to 4 months after onset. Contrast-enhanced MR was performed in four of the patients. RESULTS: Abnormal MR findings of the spinal cord included abnormal cord signal (11 of 12), best demonstrated on T2-weighted images, and morphologic changes (cord enlargement during the acute phase in nine patients and cord atrophy during the chronic phase in two), best demonstrated on T1-weighted images. Vascular abnormalities (aortic) were detected by MR in four of the 12 patients. Three of these four patients also had abnormal bone marrow signal, predominantly in the anterior half (one) or in multiple areas near the endplate and/or deep medullary portion of the vertebral body involving several vertebrae (two). T1-weighted images were not sensitive in detecting signal changes in either the bone marrow (two of three) or spinal cord (nine of 12). Enhanced MR imaging was performed in four patients (two in the acute phase and two in the chronic phase) and showed diffuse enhancement of the spinal cord proximal to a relatively unenhancing distal conus in one of the two patients imaged during the acute phase. No abnormal enhancement was noted in the other three patients. CONCLUSION: MR is a useful means of detecting spinal cord infarction and associated vascular and bony changes. The patterns of bone marrow abnormalities reflect the underlying pathophysiology of the blood supply to the spinal cord and bone. The associated vascular and bone marrow abnormalities serve as additional information for the diagnosis of spinal cord infarction.