Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7.

Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. Measures used to assess polyneuropathy in other diseases have been tested as endpoints in hATTR amyloidosis clinical trials (i.e. Neuropathy Impairment Score [NIS], NIS-lower limb, and NIS + 7), yet the unique nature of the polyneuropathy in this disease has necessitated modifications to these scales. In particular, the heterogeneous impairment and the aggressive disease course have been key drivers in developing scales that better capture the disease burden and progression of polyneuropathy in hATTR amyloidosis. The modified NIS + 7 (mNIS + 7) scale was specifically designed to assess polyneuropathy impairment in patients with hATTR amyloidosis, and has been the primary endpoint in two recent, phase III studies in this disease. The mNIS + 7 uses highly standardized, quantitative, and referenced assessments to quantify decreased muscle weakness, muscle stretch reflexes, sensory loss, and autonomic impairment. Physicians using this scale in clinical trials should be specifically trained and monitored to minimize variability. This article discusses the different scales that have been/are being used to assess polyneuropathy in patients with hATTR amyloidosis, their correlation with other disease assessments, and reflects on how and why scales have evolved to the latest iteration of mNIS + 7.

Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis.

BACKGROUND: Mutations of myelin protein zero (MPZ) may cause inherited neuropathy with variable expression. OBJECTIVE: To report phenotypic variability in a large American kindred with MPZ mutation His39Pro. PATIENTS: Genetic testing was performed on 77 family members and 200 controls. Clinical and electrophysiological field study assessments were available for review in 47 family members. RESULTS: His39Pro was found in all 10 individuals prospectively identified with neuropathy. 200 normal controls were without mutation. Symptoms of neuropathy began in adulthood and were slowly progressive except for one acute-onset painful sensory neuropathy. Associated features included premature hearing loss (n = 7), nocturnal restless leg symptoms (n = 8) and multiple sclerosis in one. CONCLUSIONS: MPZ mutation His39Pro may be associated with acute-onset neuropathy, early-onset hearing loss and restless legs. The relationship with multiple sclerosis in the proband remains uncertain.

Vibratory and cooling detection thresholds compared with other tests in diagnosing and staging diabetic neuropathy.

Increasingly more tests are being used to detect and characterize diabetic polyneuropathy, but their value in setting minimal criteria for the diagnosis of neuropathy and for staging severity remains inadequately studied. In 180 diabetics, we compared the percentage of patients with test abnormalities and associations among test results, evaluating neuropathic symptoms [neuropathy symptom score (NSS) and neuropathy scale of neuropathy symptom profile (NNSP)], deficits [neurologic disability score (NDS) and vibratory (VDT) and cooling (CDT) detection thresholds], or nerve dysfunction [nerve conduction (NC)]. The percentage of patients that were abnormal varied considerably depending on criteria for abnormality and the tests used. Abnormality (greater than or equal to 3 SD of 1 or more parameters) of NC of one or more of four nerves occurred in 80%, of two or more in 69%, of three or more in 46%, and of four in 21%. Similarly, for other tests, the rate of abnormality decreased with use of increasingly stringent criteria. Setting the criteria for abnormal NC at abnormality of two or more nerves, NSS at greater than or equal to 1, NDS at greater than 6, NNSP at greater than or equal to 97.5th percentile, and at greater than or equal to 95th percentile for the other tests, NC was abnormal in 69%, NSS in 54%, NDS in 48%, NNSP in 47%, VDT in 44%, and CDT in 35%. Abnormality of any two or more of the six tests evaluated occurred in 64% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemimasticatory spasm: clinical and electrophysiologic observations.

Hemimasticatory spasm is a rare disorder of the trigeminal nerve that produces involuntary jaw closure due to paroxysmal unilateral contraction of jaw-closing muscles. We report three patients with this disorder. Electrophysiologic studies demonstrated normal blink and masseter reflexes. The masseter inhibitory reflex was absent during periods of spasm. Needle electromyography demonstrated irregular bursts of motor unit potentials that were identical to the pattern observed in hemifacial spasm. The electrophysiologic findings suggest ectopic excitation of the trigeminal motor root or its nucleus, an abnormality that is analogous to ectopic excitation of the facial nerve in hemifacial spasm. One patient improved temporarily with surgery, one improved while on treatment with carbamazepine, and another responded favorably to botulinum toxin injection.

Trochanteric sciatic neuropathy.

A patient with severe weakness, atrophy, and sensory loss of the right leg had a focal right sciatic neuropathy. The sciatic nerve was enlarged at the level of the lesser trochanter, excessively firm, and multistranded; its stimulation threshold was focally increased. Biopsied fascicles had reduplicated perineurial leaflets, many Renaut bodies, and an abnormal unimodal spectrum of small-diameter fibers. We postulate that the lesion was induced by the combination of an underlying prominent lesser trochanter and sitting on hard benches.

Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG.

The results of clinical, radiologic, and electrophysiologic studies are retrospectively reviewed for 55 patients with neoplastic and 35 patients with radiation-induced brachial plexopathy. The presence or absence of pain as the presenting symptom, temporal profile of the illness, presence of a discrete mass on CT of the plexus, and presence of myokymic discharges on EMG contributed significantly to the prediction of the underlying cause of the brachial plexopathy. The distribution of weakness and the results of nerve conduction studies were of no help in distinguishing neoplastic from radiation-induced brachial plexopathy.

Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort.

Because there are little satisfactory data on change in severity of diabetic polyneuropathy (DP) over time from study of population-based cohorts of diabetic patients in epidemiologic surveys of DP, it is difficult to predict outcome or morbidity or to identify risk factors; it is also difficult to estimate statistical power for use in controlled clinical trials. In this longitudinal study of almost 200 patients from the Rochester Diabetic Neuropathy Study (RDNS) cohort, we assess which symptoms, clinical examinations, tests, or combinations of examinations and tests (composite scores) are best used as minimal criteria for the diagnosis of DP and as a quantitative measure of severity of DP. An abnormality (> or = 97.5th percentile) of a composite score that included the Neuropathy Impairment Score of the lower limbs plus seven tests (NIS(LL)+7 tests), was a better minimal criteria for DP than clinical judgment alone or previously published minimal criteria. First, it provided a more comprehensive assessment of neuropathic impairment. Second, it avoided the overestimated frequency of DP when the minimal criteria for DP was any one or two abnormalities from multiple measurements. Minimal criteria using nerve conduction and reduced heart beat response to deep breathing identified approximately twice as many patients with DP than did clinical examination and vibration detection threshold using CASE IV. This difference could be used to subclassify state 1 DP. Although various individual measures of DP, for example, vibration detection threshold (as evaluated by CASE IV and the 4, 2, and 1 stepping algorithm [see text]), were good measures of worsening, the composite score NIS(LL)+7 tests (assessing neuropathic impairment) was much better at showing monotone worsening. Using this composite score, the average diabetic patient in the RDNS worsened by 0.34 points per year, whereas patients with diabetic polyneuropathy worsened by 0.85 points per year. On the assumption that a therapeutic agent may prevent worsening of DP but not cause improvement, controlled clinical trials of patients with DP would need to be conducted for a period of 3 years to achieve a meaningful change of 2 NIS points (the level of abnormality considered by a Peripheral Nerve Society consensus group to be clinically meaningful).

Lack of progression of neurologic deficit in survivors of paralytic polio: a 5-year prospective population-based study.

We completed a prospective, population-based cohort study of polio survivors in Olmsted County, Minnesota, between 1986 and 1993. We identified 50 individuals who had had paralytic polio between 1935 and 1960, as representative of all 300 cases of paralytic polio in the county. We completed detailed quantitative clinical and electrophysiologic studies at entry and after 5 years. These studies demonstrated stable neuromuscular function within the cohort, although 60% of the individuals were symptomatic. In two-thirds of the symptomatic patients, the causes of their symptoms were unrelated to earlier polio. For the 20% of patients who had unexplained muscle pain, perception of weakness, and fatigue, a mechanical disorder most likely underlies their symptoms.

Variables influencing neuropathic endpoints: the Rochester Diabetic Neuropathy Study of Healthy Subjects.

We determined the normal limits for various neuropathic tests in healthy subjects. The study, the Rochester Diabetic Neuropathy Study (RDNS), is noteworthy because of its size (more than 400 subjects), random selection of subjects, and selection of at least 15 men and 15 women without neuropathy, neurologic disease, or diseases predisposing to neuropathy from each hemidecade between 18 and 74 years of age from the population of a defined region (Rochester, MN). Subjects were classified into those with (nonhealthy subjects, RDNS-NS) and without (healthy subjects, RDNS-HS) neuropathy, neurologic or psychiatric disease, or diseases known to predispose to neuropathy. The study provides normal limits for tests used in the RDNS but it has broader uses as well. We found that (1) less than 10% of subjects in the third decade, approximately 20% in the fourth decade, and approximately 30% in the fifth or older decades were placed into the RDNS-NS category; (2) healthy subjects (RDNS-HS) retain their ability to walk on toes and heels regardless of age, excessive weight, or lack of physical fitness, but not their ability to arise from a kneeled position--lost in more than 5% of persons 60 years and older; (3) the frequency of decreased or absent ankle reflexes exceeds 5% in healthy subjects older than 50 years--limiting their value as a sign of diabetic polyneuropathy and necessitating a grading change with age in the neuropathy impairment score.(ABSTRACT TRUNCATED AT 250 WORDS)

Late effects of paralytic poliomyelitis in Olmsted County, Minnesota.

We identified a cohort of 300 individuals who had paralytic polio between 1935 and 1955. All lived in Olmsted County, Minnesota. From the 247 survivors, we selected 50 subjects for detailed historical, functional, psychological, clinical, and electrophysiologic evaluation. Sixty-four percent of these 50 survivors complained of new symptoms of muscle pain, fatigue, and weakness after a period of prolonged stability. This led to changes in lifestyle or activity in only 18%. The likelihood of expressing new complaints was not related to present age or interval since polio, and electrophysiologic testing did not distinguish between those with or without new problems. The development of new difficulties in a limb was most strongly predicted by significant paralysis of that limb at the time of the acute illness. Patients with leg weakness were twice as likely to complain of new problems compared to those with arm weakness. Elevated creatine kinase levels were present only in those with new complaints.

Effect of BAEP monitoring on hearing preservation during acoustic neuroma resection.

We measured the effect of brainstem auditory evoked potential (BAEP) monitoring on hearing preservation in acoustic neuroma resection in 90 consecutive patients with monitoring compared with 90 historical controls matched for tumor size and preoperative hearing status. In small tumors (less than 2 cm), BAEP monitoring was associated with a higher rate of hearing preservation and a greater chance that the hearing preserved was clinically useful. Changes in the BAEP intraoperatively showed a good correlation with postoperative hearing status.

The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity.

We evaluated the initial assessments of the 380 diabetic patients with and without polyneuropathy in the Rochester Diabetic Neuropathy Study for (1) associations among neuropathy test results, (2) usefulness of different tests for diagnosing and staging polyneuropathy, (3) appropriateness of different minimal criteria for the diagnosis of polyneuropathy, and (4) significant differences in test results with increasing stage of polyneuropathy. Nerve conduction ([NC]; abnormality in two or more nerves) and quantitative autonomic examination ([QAE]; decreased heart-beat response to deep breathing [DB] or the Valsalva maneuver [VAL]) were the most sensitive and objective and were especially suitable for detection of subclinical neuropathy. We propose the following minimal criteria for the diagnosis of diabetic polyneuropathy: greater than or equal to 2 abnormal evaluations (from among neuropathic symptoms, neuropathic deficits, NC, quantitative sensory examination [QSE], and QAE) with one of the two being abnormality of NC or QAE (DB or VAL). Neuropathy Symptom Score, Neuropathy Disability Score, QSE (vibratory or cooling detection threshold), and summated compound muscle action potential of ulnar, peroneal, and tibial nerves were best for judging severity. Inability to walk on heels provided a discrete separation of diabetic patients into those with mild and those with more severe neuropathy--a separation helpful in staging.

Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group.

BACKGROUND: Preclinical studies have demonstrated that nerve growth factor may prevent or reverse peripheral neuropathy. We have therefore tested the effects of recombinant human nerve growth factor in patients with diabetic polyneuropathy. METHODS: A total of 250 patients with symptomatic diabetic polyneuropathy randomly received either placebo or one of two doses of recombinant human nerve growth factor for 6 months. Patients were assessed for symptoms and signs of polyneuropathy before and after treatment. RESULTS: Compared with placebo, recombinant human nerve growth factor led to significant improvement after 6 months of treatment, as measured by the sensory component of the neurologic examination, two quantitative sensory tests, and the impression of most subjects that their neuropathy had improved. Three prospectively identified multiple endpoint analyses indicated improvements in the nerve growth factor treatment groups over the placebo group in all three analyses (p = 0.032; p = 0.008; p = 0.005). Recombinant human nerve growth factor was well tolerated, with injection site discomfort reported as the most frequent adverse event. CONCLUSIONS: Recombinant human nerve growth factor appears to be safe and shows preliminary evidence of efficacy in patients with symptomatic diabetic polyneuropathy.

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.

A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester, MN--The Rochester Diabetic Neuropathy Study (RDNS)--is population-based and uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy. Nondiabetic persons, drawn from the same population, serve as controls. For patients 10 to 70 years old, the RDNS cohort is representative of diabetics living in Rochester, MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (rI) as a measure of test reproducibility, we found high rI (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observers for NDS and the W-NDS.

Physiological prediction of muscle forces--I. Theoretical formulation.

A physiological model for predicting muscle forces is described. Rigid-body mechanics and musculoskeletal physiology are used to describe the dynamics of the segment model and muscle model. Unknown muscle and joint contact forces outnumber the equilibrium equations resulting in an indeterminate problem. Mathematical optimization is utilized to resolve the indeterminacy. The modeling procedure relies entirely on established physiological principles. Data describing the muscle anatomy and body structures are included. A model defining the force-length-velocity-activation relationship of a muscle is adopted. The force a muscle produces is assumed to be proportional to its maximum stress, physiological cross-sectional area, activation, and its functional configurations including the muscle architecture, muscle length, contracting velocity, and passive tension. These factors are incorporated into inequality equations which limit the force for each muscle. Minimal muscular activation is forwarded as the optimization criterion for muscle force determination.

Physiological prediction of muscle forces--II. Application to isokinetic exercise.

The successful application of a physiological model of the musculoskeletal system capable of accounting for nonequilibrium dynamic loading and predicting individual muscle forces in the knee is presented. The model incorporates rigid-body mechanics and musculoskeletal physiology. Unknown muscle and joint contact forces outnumber the equilibrium equations resulting in an indeterminant problem. Mathematical optimization is utilized to resolve the indeterminacy. The model is used to estimate individual muscle forces during isokinetic exercise. Five subjects were tested at speeds of 60 degrees/s and 180 degrees/s. A newly proposed optimal criterion, minimizing muscular activation, results in muscle force predictions which have significantly higher correlations with myoelectric activity than other linear and nonlinear optimal criteria. The results demonstrate that properly constrained linear programming methods do not limit the number of active muscles and allow for uniform recruitment of the active muscles.

Selective peripheral denervation for torticollis: preliminary results.

Herein we report the preliminary results in nine patients who have undergone selective peripheral denervation for spasmodic torticollis and have been followed up for at least 13 months. All patients had improvement immediately after surgical intervention, and the results have been maintained in five patients. In one patient who had recurrent torticollis, a second procedure in conjunction with injection of botulinum toxin has produced substantial improvement; however, follow-up was brief (6 months). No surgical complications occurred. We believe that selective peripheral denervation is safe and that it can benefit patients with torticollis who have not responded to other types of therapy. These favorable results confirm other published reports on the efficacy of selective peripheral denervation. Long-term follow-up, however, is necessary for determining the role of this procedure in the management of torticollis.

The clinical spectrum of critical illness polyneuropathy.

OBJECTIVE: To describe the entity of critical illness polyneuropathy and review our experience with six cases. DESIGN: We present case reports of six patients with polyneuropathy associated with critical illness, who received medical care at the Mayo Clinic between 1992 and 1994, and discuss similar cases from the literature. RESULTS: Critical illness may damage peripheral nerves. In previous studies, sepsis and multiorgan failure have been found to trigger a peripheral neuropathy. Of our six patients with critical illness polyneuropathy, all had a preceding severe bacterial infection or septic shock. In one patient who had long-term administration of vecuronium bromide and had received massive intravenous doses of corticosteroids, sural nerve and quadriceps muscle biopsy specimens were available; they revealed axonal neuropathy and notable myopathic changes, respectively. The outcome was good in patients who survived the critical illness. CONCLUSION: Polyneuropathy in critically ill patients may be a cause of severe generalized limb weakness and occurs in the setting of a sepsis syndrome. The long-term outcome is good in patients who recover from the underlying critical illness. Compression neuropathies may be a cause of permanent sequelae.

Subacute diabetic proximal neuropathy.

OBJECTIVE: To evaluate the clinical, electrophysiologic, autonomic, and neuropathologic characteristics and the natural history of subacute diabetic proximal neuropathy and its response to immunotherapy. MATERIAL AND METHODS: For the 12-year period from 1983 to 1995, we conducted a retrospective review of medical records of Mayo Clinic patients with diabetes who had subacute onset and progression of proximal weakness. The responses of treated versus untreated patients were compared statistically. RESULTS: During the designated study period, 44 patients with subacute diabetic proximal neuropathy were encountered. Most patients were middle-aged or elderly, and no sex preponderance was noted. The proximal muscle weakness often was associated with reduced or absent lower extremity reflexes. Associated weight loss was a common finding. Frequently, patients had some evidence of demyelination on nerve conduction studies, but it invariably was accompanied by concomitant axonal degeneration. The cerebrospinal fluid protein concentration was usually increased. Diffuse and substantial autonomic failure was generally present. In most cases, a sural nerve biopsy specimen suggested demyelination, although evidence of an inflammatory infiltrate was less common. Of 12 patients who received treatment (with prednisone, intravenous immune globulin, or plasma exchange), 9 had improvement of their conditions, but 17 of 29 untreated patients (59%) with follow-up also eventually had improvement, albeit at a much slower rate. Improvement was usually incomplete. CONCLUSION: We suggest that the entity of subacute diabetic proximal neuropathy is an extensive and severe variant of bilateral lumbosacral radiculoplexopathy, with some features suggestive of an immune-mediated cause. It differs from chronic inflammatory demyelinating polyradiculoneuropathy in that most cases have a more restricted distribution and seem to be monophasic and self-limiting. The efficacy of immunotherapy is unproved, but such intervention may be considered in the severe and progressive cases or ones associated with severe neuropathic pain.