Neuropathy Impairment Score of the Lower Limb (NIS-LL)



Coelho T, Maia L, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Supplementary Material Classification of EvidenceDoes 18 months of treatment with tafamidis 20 mg QD reduce clinical progression in patients with transthyretin familial amyloid polyneuropathy (TTR-FAP), as measured by 2 primary outcomes, the neuropathy impairment score–lower limbs (NIS-LL) and the Norfolk quality of life–diabetic neuropathy (QOL-DN) score? This study provides Class II evidence that 20 mg tafamidis QD was associated with a nonsignificant decrease in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.MethodsThis supplemental material provides a description of the outcome measures used for the coprimary endpoints—NIS-LL and the Norfolk QOL-DN score, and outcome measures used for the secondary endpoints in the study.Neuropathy Impairment Score of the Lower Limb (NIS-LL) The NIS is a composite clinical scoring system that has been widely used to objectively assess the severity of peripheral neuropathy. The NIS-LL is a subset of the NIS that assesses function of the lower limbs, the extremities most affected early in TTR-FAP disease progression. The NIS-LL quantifies the findings of the neurologic examination by attributing a score (ranging from 0 [normal] to 88 [total impairment]) to the clinical abnormalities noted in the physical assessment of sensation, muscle power, and tendon reflexes. Each component of the NIS-LL measures a different attribute of peripheral nervous system function, all of which are believed to have merit in the assessment of the complex system that controls human movement. The components of the NIS-LL include the following:Sensation (touch pressure, pinprick, vibration, joint position). The components of the sensory examination, except for joint position, are assessed on the dorsal surface at the base of the right and left great toenails. Joint position is assessed by moving the terminal phalanx of the right and left great toes. Sensory assessment is scored as 0 (normal), 1 (decreased), or 2 (absent). As assessments are performed on the right and left feet, the maximum total score possible for the sensory component is 16.Reflexes (quadriceps femoris, triceps surae [Achilles]). Reflex assessment is scored as 0 (normal), 1 (decreased), or 2 (absent). Adjustment is made for the age of the patient (eg, absent reflexes in a patient older than 60 years of age is assessed as 0, or normal). As assessments are performed on the right and left feet, the maximum total score possible for the reflex component is 8.Muscle weakness (hip flexion, hip extension, knee flexion, knee extension, ankle dorsiflexors, ankle planter flexors, toe extensors, toe flexors). Muscle weakness is scored as 0 (normal), 1 (25% weak), 2 (50% weak), 3 (75% weak), 3.25 (move against gravity), 3.5 (movement, gravity eliminated), 3.75 (muscle flicker, no movement), or 4 (paralysis). As assessments are performed on the right and left lower extremities, the maximum total score possible for the muscle component is 64.Norfolk QOL-DNThe Norfolk QOL-DN is a self-administered questionnaire that quantifies the impact of neuropathy on patients’ QOL. The 35 scored questions are numbered items that comprise the entire (total) scale, or TQOL, to yield a score of –2 to 138. Each item is attributed to 1 of the following 5 domains:Physical functioning/large-fiber neuropathy. Functions related to large-nerve fibers, including motor function, and those sensory functions related to large sensory fibers, especially tactile discrimination.Activities of daily living (ADLs). Items associated with the impact of neuropathy on routine activities of daily life, related to large-fiber function.Symptoms. An inventory of the common symptoms of neuropathy at each of 4 body sites (feet, legs, hands, and arms).Small-fiber neuropathy. Sensory function related to pain and loss of thermal sensation.Autonomic nerve function. Neuropathy-related items, including orthostasis, gastrointestinal, and genitourinary functions.The scores across the 5 domains are summed to provide the TQOL score. The Norfolk QOL-DN was shown to discriminate the presence of neuropathy and distinguish among 5 neuropathic disease stages in a population of German patients with diabetic polyneuropathy.e ADDIN EN.CITE <EndNote><Cite><Author>Vinik</Author><Year>2008</Year><RecNum>14</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="ew5wx0tpnt9r9mefswspzre9rda9vvt02ze0">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vinik, E. J.</author><author>Paulson, J. F.</author><author>Ford-Molvik, S. L.</author><author>Vinik, A. I.</author></authors></contributors><auth-address>Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, Virginia, USA.</auth-address><titles><title>German-translated Norfolk quality of life (QOL-DN) identifies the same factors as the English version of the tool and discriminates different levels of neuropathy severity</title><secondary-title>J Diabetes Sci Technol</secondary-title></titles><periodical><full-title>J Diabetes Sci Technol</full-title></periodical><pages>1075-86</pages><volume>2</volume><number>6</number><edition>2009/11/04</edition><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1932-2968 (Electronic)&#xD;1932-2968 (Linking)</isbn><accession-num>19885296</accession-num><urls><related-urls><url> The Norfolk QOL-DN underwent linguistic validation for each country and language.Summated 7-nerve tests–normal deviates (Σ7 NTs nds)The Σ7 NTs nds combines results from 5 nerve conduction studies (sural nerve sensory nerve action potential, peroneal nerve compound muscle action potential, peroneal nerve motor conduction velocity, peroneal nerve distal motor latency, and tibial distal motor latency) with vibration detection threshold (VDT) of the hallux, and heart rate response to deep breathing (HRDB) at 6 breaths/minute. The components of the Σ7 NTs nds are primarily measures of large-fiber function. The score ranges from –26 (extreme normal function) to 26 (extreme abnormal function). HRDB is a sensitive measure of parasympathetic cardiac control, and normative values by age have been determined. Summated 3-nerve tests–small-fiber normal deviates (Σ3 NTSF nds) The Σ3 NTSF nds includes 3 assessments of small-fiber function: cooling detection threshold (CDT), heat/pain detection threshold (HPDT), and HRDB. All were assessed using the Computer Aided Sensory Evaluator V4, a computerized test of sensory threshold determination. The thermal sensations of cooling and heat pain assess small myelinated and unmyelinated sensory nerve function. The score ranges from –11.2 (extreme normal function) to 11.2 (extreme abnormal function).Modified body mass index (mBMI)mBMI is obtained by multiplying the BMI (weight [kg]/height2 [m2]) by serum albumin concentration (g/L). As an endpoint, mBMI may be more reflective of nutritional status than BMI because it corrects for the effect of edema due to low serum albumin level on BMI.e ADDIN EN.CITE <EndNote><Cite><Author>Suhr</Author><Year>1994</Year><RecNum>15</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="ew5wx0tpnt9r9mefswspzre9rda9vvt02ze0">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Suhr, O.</author><author>Danielsson, A.</author><author>Holmgren, G.</author><author>Steen, L.</author></authors></contributors><auth-address>Section of Gastroenterology, University Hospital, Sweden.</auth-address><titles><title>Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy</title><secondary-title>J Intern Med</secondary-title></titles><periodical><full-title>J Intern Med</full-title></periodical><pages>479-85</pages><volume>235</volume><number>5</number><edition>1994/05/01</edition><keywords><keyword>Adult</keyword><keyword>Amyloid Neuropathies/*complications/*mortality</keyword><keyword>Female</keyword><keyword>Gastrointestinal Diseases/*complications</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Nutrition Disorders/*complications</keyword><keyword>Prognosis</keyword><keyword>Prospective Studies</keyword><keyword>Retrospective Studies</keyword><keyword>Statistics as Topic</keyword><keyword>Survival Analysis</keyword><keyword>Time Factors</keyword></keywords><dates><year>1994</year><pub-dates><date>May</date></pub-dates></dates><isbn>0954-6820 (Print)&#xD;0954-6820 (Linking)</isbn><accession-num>8182405</accession-num><urls><related-urls><url> e-1. Patient demographics and baseline dataCharacteristicTafamidis(n = 64)Placebo(n = 61)Men, n (%)32 (50)26 (43)Age, yrMean ± SD39.8 ± 12.738.4 ± 12.9Race/ethnicity, n (%)Caucasian56 (88)54 (89)Latino6 (9)6 (10)Other2 (3)1 (2)mBMI (BMI × serum albumin)Mean ± SD1004.6 ± 165.201011.5 ± 212.92Median974.7983.825th, 75th percentile867.2, 1155.1896.4, 1094.7Disease duration, moMean ± SD47.0 ± 48.4034.7 ± 32.88Median28.021.025th, 75th percentile13.8, 41.713.5, 72.2NIS-LL (range, 0–88)Mean ± SD8.4 ± 11.4011.4 ± 13.54Median4.06.025th, 75th percentile0.0, 13.02.0, 9.3Norfolk QOL-DN (TQOL) (range, –2 to 138)Mean ± SD27.3 ± 24.1730.8 ± 26.7Median19.022.025th, 75th percentile11.0, 40.010.0, 43.5Σ7 NTs nds (large-fiber range, –26 to 26)Mean ± SD7.8 ± 9.18.7 ± 8.5Median7.49.725th, 75th percentile1.0, 15.01.0, 15.0Σ3 NTSF nds (small-fiber range, –11.2 to 11.2)Mean ± SD5.5 ± 4.55.6 ± 4.1Median4.85.025th, 75th percentile1.8, 11.22.0, 9.1Table e-2. Most common AEs.*EventTafamidis (n = 65)Placebo (n = 63)Subjects, n (%)Subjects with ≥1 AE60 (92.3)61 (96.8)Diarrhea17 (26.2)11 (17.5)Urinary tract infection15 (23.1)8 (12.7)Pain in extremity11 (16.9)6 (9.5)Influenza10 (15.4)9 (14.3)Headache10 (15.4)12 (19.0)Nasopharyngitis9 (13.8)8 (12.7)Upper abdominal pain 8 (12.3)2 (3.2)Nausea8 (12.3)8 (12.7)Vomiting7 (10.8)8 (12.7)Lacrimation decreased6 (9.2)7 (11.1)Myalgia5 (7.7)2 (3.2)Punctate keratitis5 (7.7)3 (4.8)Back pain5 (7.7)4 (6.3)Vaginal infection4 (6.2)1 (1.6)Peripheral edema4 (6.2)8 (12.7)Constipation4 (6.2)7 (11.1)Pharyngitis4 (6.2)5 (7.9)Upper respiratory tract infection4 (6.2)3 (4.8)Thermal burn4 (6.2)5 (7.9)Anxiety4 (6.2)3 (4.8)Depression4 (6.2)3 (4.8)Erectile dysfunction4 (6.2)4 (6.3)Paresthesia3 (4.6)10 (15.9)Abdominal pain3 (4.6)5 (7.9)Weight decreased3 (4.6)5 (7.9)Vertigo3 (4.6)4 (6.3)Neuralgia2 (3.1)12 (19.0)Pharyngolaryngeal pain2 (3.1)7 (11.1)Muscle spasms2 (3.1)7 (11.1)AV block, first degree2 (3.1)6 (9.5)Dizziness2 (3.1)4 (6.3)Hypoesthesia1 (1.5)4 (6.3)Fatigue0 (0.0)6 (9.5)Anemia0 (0.0)5 (7.9)*Reported by >5% of subjects in either treatment group.Figure e-1. Patient disposition and analysis populations. AE = adverse event; I/E = inclusion/exclusion criteria; ITT = intent-to-treat; VDT = vibration detection threshold.e-References ADDIN EN.REFLIST 1.Vinik EJ, Paulson JF, Ford-Molvik SL, Vinik AI. German-translated Norfolk quality of life (QOL-DN) identifies the same factors as the English version of the tool and discriminates different levels of neuropathy severity. J Diabetes Sci Technol 2008;2:1075-1086.2.Suhr O, Danielsson A, Holmgren G, Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J Intern Med 1994;235:479-485. ................
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