Erik Nordh

Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial

IMPORTANCE Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294671.

Reproducibility and influence of test modality order on thermal perception and thermal pain thresholds in quantitative sensory testing

OBJECTIVE To evaluate the reproducibility of quantitative sensory testing (QST), performed with the method-of-limits (MLI) at different test intervals, by assessing the inter- and intra-individual variation of thermal cold (CT) and warm (WT) perception thresholds, and of thermal cold- (CPT) and heat pain (HPT) thresholds. METHODS QST with the MLI was performed in 38 healthy subjects in three repeated and pseudo-randomized test sessions, done at three occasions (days 1, 2 and 7). RESULTS At repeated testing, none of the thermal threshold estimates showed systematic significant differences, neither between days nor between sessions within the same day, when determined as first tests (FT), and for CT and WT also after thermal pain assessment (aTPA). However, when determined directly aTPA, both CT and WT were noted significantly higher. Also the coefficients of variation and repeatability showed increased values aTPA. CONCLUSIONS The high reproducibility show that the MLI is a feasible method for thermal QST, with reproducible results both at shorter and longer test intervals, on condition that temperature thresholds are determined before any painful thermal stimuli are given, as the latter influence both CT and WT assessments. SIGNIFICANCE The findings show that QST with the MLI is a reliable tool for indirect evaluation of human small nerve fiber function.

Clinical evaluation of a resorbable wrap-around implant as an alternative to nerve repair : A prospective, assessor-blinded, randomised clinical study of sensory, motor and functional recovery after peripheral nerve repair.

Peripheral nerve injures are common and often result in impaired functional recovery. The majority of injuries involve the arm and/or the hand. The traditional treatment for peripheral nerve injuries is repair by using microsurgical techniques, either by primary nerve suture or nerve graft, but research to find more successful methods that could improve recovery is ongoing. Tubulisation has been investigated by several authors and is suggested as an alternative to microsurgical techniques. The resorbable poly[(R)-3-hydroxybutyrate] (PHB) is one of the materials that has been previously tested experimentally. In this prospective, randomised, assessor-blinded clinical study, PHB was investigated as an alternative to epineural suturing in the treatment of peripheral nerve injuries at the wrist/forearm level of the arm. Twelve patients, with a complete, common, sharp injury of the median and/or ulnar nerve at the wrist/forearm level, were treated by either using PHB or microsurgical epineural end-to-end suturing. All patients were assessed using a battery of tests, including evaluation of functional, sensory and motor recovery by means of clinical, neurophysiological, morphological and physiological evaluations at 2 weeks and 3, 6, 9, 12 and 18 months after surgery. No adverse events or complications considered as product related were reported, and thus PHB can be regarded as a safe alternative for microsurgical epineural suturing. The majority of the methods in the test battery showed no significant differences between the treatment groups, but one should consider that the study involved a limited number of patients and a high variability was reported for the evaluating techniques. However, sensory recovery, according to the British Medical Research Council score and parts of the manual muscle test, suggested that treating with PHB may be advantageous as compared to epineural suturing. This, however, should be confirmed by large-scale efficacy studies.

A flexible high-precision video system for digital recording of motor acts through lightweight reflex markers

This paper describes and evaluates the digital MacReflex system for wireless recording of movements in three dimensions. Up to seven high resolution infra-red sensitive CCD video cameras with electronic shutters register the positions of maximally 40 stroboscopically illuminated retro-reflective tape markers. The system is equipped with real-time video processors for computation of position co-ordinates for the markers and for optimised data transmission and storage. Data are output to any type of computer through a standard serial interface, which also provides possibilities for simultaneous A/D-sampling. Dynamic manipulation of the recorded signals in three-dimensional plots is provided by standard software and transformation and evaluation of recorded data are performed in standard software. The described equipment is found to offer a flexible and easily operated solution for recording of movements with high resolution.

Sensory recovery after hand reimplantation: a clinical, morphological, and neurophysiological study in humans.

Despite fairly good return of motor function, patients who have amputated hands reimplanted demonstrate poor sensory recovery and severe cold intolerance, two variables that are difficult to quantify reliably. In this study we wanted to find out if there is a correlation between morphological findings of sensory and sympathetic reinnervation and clinical and neurophysiological variables. Skin was biopsied from the reimplanted and corresponding area in the normal hands of eight patients who had sustained a hand amputation and subsequent reimplantation. The sections were immunostained using markers for both sensory and sympathetic nerve fibres. Comparison between the reimplanted and normal sides in each individual showed a mean loss of sensory immunoreactive nerve fibres of 30%, and for sympathetic immunoreactivity the loss was 60%. There was measurable two-point discrimination in the injured hand only in patients below the age of 40 years, corresponding to the better recovery of mechanical thresholds evaluated neurophysiologically for this age group. These results confirm the extensive loss of sensory nerve fibres after nerve injury, probably correlated to loss of sensory neurons. We have also shown that it is possible to correlate the results of clinical and neurophysiological evaluation with morphological results of skin reinnervation specific to the repaired nerve, and so improve the possibility for the quantification of sensory recovery.

Spatiotemporal consistency of human mandibular and head-neck movement trajectories during jaw opening-closing tasks

Previous studies of spatial and temporal coordination between human mandibular and head-neck movements during single as well as rhythmic jaw opening-closing tasks suggest that these movements are regulated by central nervous commands common for jaw and neck muscles. The present study evaluated the spatiotemporal consistency of concomitant mandibular and head-neck movements during repeated single jaw opening-closing tasks, in short- as well as long-term perspectives and at different speeds. The subjects were seated in an upright position without head support. They were instructed to perform single maximal jaw opening-closing movements, repeated ten times for fast and slow speed, respectively. Recordings were made at two sessions. A wireless optoelectronic technique was used to record three-dimensional mandibular and head-neck movements. The spatiotemporal consistency of repeated movement trajectories of the mandible (both in relation to the head and in space) and of the head-neck was quantitatively assessed by a spatiotemporal index (STI). In addition, mean movement trajectory patterns were compared for speed and recording sessions (expressed as correlation coefficient, r). The results showed relatively small STI (high degree of spatiotemporal consistency) and high r (reproducible trajectory patterns) values, both in short- and long-term perspectives, for concomitant mandibular and head-neck movements. The data were not generally speed related. In conclusion, the present results suggest a high degree of spatiotemporal consistency of the kinematic patterns of mandibular and head-neck movements during jaw opening-closing, in short- as well as long-term perspectives. They also indicate that underlying neural processes are invariant in nature. The results give further support to the notion of a tight functional coupling between the human jaw and the neck motor systems during natural jaw function.

Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus in Patients with Parkinson's Disease: Effects on Diadochokinetic Rate

The hypokinetic dysarthria observed in Parkinsons disease (PD) affects the range, speed, and accuracy of articulatory gestures in patients, reducing the perceived quality of speech acoustic output in continuous speech. Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) and of the caudal zona incerta (cZi-DBS) are current surgical treatment options for PD. This study aimed at investigating the outcome of STN-DBS (7 patients) and cZi-DBS (7 patients) in two articulatory diadochokinesis tasks (AMR and SMR) using measurements of articulation rate and quality of the plosive consonants (using the percent measurable VOT metric). The results indicate that patients receiving STN-DBS increased in articulation rate in the Stim-ON condition in the AMR task only, with no effect on production quality. Patients receiving cZi-DBS decreased in articulation rate in the Stim-ON condition and further showed a reduction in production quality. The data therefore suggest that cZi-DBS is more detrimental for extended articulatory movements than STN-DBS.

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 ≤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. Muscle Nerve, 2006

Head Immobilization can Impair Jaw Function

Findings that jaw-opening/-closing relies on both mandibular and head movements suggest that jaw and neck muscles are jointly activated in jaw function. This study tested the hypothesis that rhythmic jaw activities involve an active repositioning of the head, and that head fixation can impair jaw function. Concomitant mandibular and head-neck movements were recorded during rhythmic jaw activities in 12 healthy adults, with and without fixation of the head. In four participants, the movement recording was combined with simultaneous registration of myoelectric activity in jaw and neck muscles. The results showed neck muscle activity during jaw opening with and without head fixation. Notably, head fixation led to reduced mandibular movements and shorter duration of jaw-opening/-closing cycles. The findings suggest recruitment of neck muscles in jaw activities, and that head fixation can impair jaw function. The results underline the jaw and neck neuromuscular relationship in jaw function.

Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus in Patients with Parkinson's Disease: Effects on Voice Intensity

Deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinsons disease (PD) affects speech inconsistently. Recently, stimulation of the caudal zona incerta (cZi-DBS) has shown superior motor outcomes for PD patients, but effects on speech have not been systematically investigated. The aim of this study was to compare the effects of cZi-DBS and STN-DBS on voice intensity in PD patients. Mean intensity during reading and intensity decay during rapid syllable repetition were measured for STN-DBS and cZi-DBS patients (eight patients per group), before- and 12 months after-surgery on- and off-stimulation. For mean intensity, there were small significant differences on- versus off-stimulation in each group: 74.2 (2.0) dB contra 72.1 (2.2) dB (P = .002) for STN-DBS, and 71.6 (4.1) dB contra 72.8 (3.4) dB (P = .03) for cZi-DBS, with significant interaction (P < .001). Intensity decay showed no significant changes. The subtle differences found for mean intensity suggest that STN-DBS and cZi-DBS may influence voice intensity differently.