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.

The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders.

BACKGROUND: Hereditary motor and sensory neuropathy type 2C (HMSN2C, Charcot-Marie-Tooth 2C [CMT2C]) is an autosomal dominant motor and sensory neuropathy involving limb, diaphragm, vocal cord, and intercostal muscles. OBJECTIVE: To identify the chromosome localization for this disorder in one large American family of English and Scottish ethnicity. METHODS: Variable clinical severity led the authors to combine several approaches to accurately identify affected patients. Genome-wide two-point linkage analysis, high-definition mapping, and multipoint and recombinant haplotype analyses were performed. Mutation analysis of the triplet repeat region of ataxin-2 was also carried out. RESULTS: The initial genome-wide scan identified a region at 12q24, and fine mapping provided a maximal lod score of 4.73 (D12S1645 and D12S1583 at theta = 0.01 and 0, respectively). With multipoint analysis, a higher lod score of 5.17 was obtained and localized to the same region at 119.0 cM. Haplotype analysis narrowed the region to approximately 5.0 cM between D12S1646,D12S1330 and D12S105,D12S1339 (12q23.3-24.21). Ataxin-2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), localizes to this region, but no triplet repeat expansion or point mutations within the repeat were found. CONCLUSIONS: The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.

Guamanian neurodegenerative disease: electrophysiologic findings.

Amyotrophic lateral sclerosis (ALS), parkinsonism and/or dementia are highly prevalent among the Chamorro population of Guam. The incidence of Guamanian ALS has markedly declined in recent years, but these incidence figures may reflect underascertainment of subclinical disease. Guamanian Chamorro patients have not been systematically studied using modern clinical neurophysiological techniques. Electromyography (EMG: needle exam and nerve conduction studies) was used to study 29 patients with the major subtypes of Guamanian neurodegenerative disease, as well as 11 neurologically normal Guamanian Chamorro subjects. Central conduction was assessed by somatosensory evoked potentials (SEP's) in 16 patients. EMG evidence of peripheral neuropathy, (often subclinical) was found in 45% of Guamanian patients but no Chamorro control subjects. Diabetes mellitus, which is highly prevalent in this population, was present in some, but not all of these cases. Clinically unsuspected motor neuron disease was identified by EMG in only one of the 23 Guamanian patients with parkinsonism and/or dementia and in none of the 11 Chamorro control subjects. Two of seven patients with the clinical phenotype of Guamanian ALS had a more benign EMG pattern on the needle electrode exam with absence of fibrillation and fasciculation potentials. Three of 16 patients (all with parkinsonism and dementia) had mildly abnormal tibial SEP's. No patient had EMG evidence of myopathy or a defect of neuromuscular transmission. We conclude: (1) peripheral neuropathy may be a manifestation of Guamanian neurodegenerative disease; (2) the declining prevalence of ALS on Guam is not associated with the development of a subclinical form of motor neuron disease; (3) the substantial overlap of Guamanian ALS with parkinsonism-dementia reported in prior decades is no longer apparent; (4) abnormal central conduction, as assessed by tibial SEP's, is present in some patients with Guamanian parkinsonism-dementia.

In-vivo function of the thumb muscles.

OBJECTIVE: The purpose of this study is to quantify the electrical activity of the thumb muscles responsible for the production of force in different directions of thumb movement. DESIGN: The isometric forces and electromyographic activity generated by seven thumb muscles were measured on five normal healthy test subjects. BACKGROUND: The thumb is very important for proper hand function. Presently available electromyographic studies of the thumb muscles provide only limited information. Most thumb muscles have more than one function. Additional studies are required to carefully examine and confirm the in-vivo relationship between the thumb muscle electromyogram and mechanical output. METHODS: The direction and magnitude of the force vector generated at the interphalangeal joint and the relative electrical activity were obtained for eight directions of thumb action. The regions of function were defined for the abductor pollicis brevis, opponens pollicis, flexor pollicis brevis, adductor pollicis, flexor pollicis longus, extensor pollicis longus, and the abductor pollicis longus. Data was collected during voluntary isometric contraction, both before and after blocking the median nerve at the wrist. RESULTS: The highest force production was obtained during flexion. The region of maximal muscle electrical activity varied for each muscle studied. The areas of maximal in-vivo muscle activity agreed with the moment arm data reported in the literature. The median nerve block eliminated the ability to produce force in abduction. CONCLUSIONS: This study has demonstrated that by combining electromyographic measurement and biomechanical analysis it is possible to confirm the relationship between in-vivo thumb muscle function and muscle mechanics in a novel manner. The findings of this study indicate the importance of the local anatomy in controlling the direction of force production.

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.

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.

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).

Randomized prospective trial comparing ileal pouch-anal anastomosis performed by excising the anal mucosa to ileal pouch-anal anastomosis performed by preserving the anal mucosa.

OBJECTIVE: The purpose of the study is to compare the results of ileal pouch-anal anastomosis (IPAA) in patients in whom the anal mucosa is excised by handsewn techniques to those in whom the mucosa is preserved using stapling techniques. SUMMARY BACKGROUND DATA: Ileal pouch-anal anastomosis is the operation of choice for patients with chronic ulcerative colitis requiring proctocolectomy. Controversy exists over whether preserving the transitional mucosa of the anal canal improves outcomes. METHODS: Forty-one patients (23 men, 18 women) were randomized to either endorectal mucosectomy and handsewn IPAA or to double-stapled IPAA, which spared the anal transition zone. All patients were diverted for 2 to 3 months. Nine patients were excluded. Preoperative functional status was assessed by questionnaire and anal manometry. Twenty-four patients underwent more extensive physiologic evaluation, including scintigraphic anopouch angle studies and pudendel never terminal motor latency a mean of 6 months after surgery. Quality of life similarly was estimated before surgery and after surgery. Univariate analysis using Wilcoxon test was used to assess differences between groups. RESULTS: The two groups were identical demographically. Overall outcomes in both groups were good. Thirty-three percent of patients who underwent the handsewn technique and 35% of patients who underwent the double-stapled technique experienced a postoperative complication. Resting anal canal pressures were higher in the patients who underwent the stapled technique, but other physiologic parameters were similar between groups. Night-time fecal incontinence occurred less frequently in the stapled group but not significantly. The number of stools per 24 hours decreased from preoperative values in both groups. After IPAA, quality of life improved promptly in both groups. CONCLUSIONS: Stapled IPAA, which preserves the mucosa of the anal transition zone, confers no apparent early advantage in terms of decreased stool frequency or fewer episodes of fecal incontinence compared to handsewn IPAA, which excises the mucosa. Higher resting pressures in the stapled group coupled with a trend toward less night-time incontinence, however, may portend better function in the stapled group over time. Both operations are safe and result in rapid and profound improvement in quality of life.

Neuromuscular complications associated with liver transplantation.

We studied neuromuscular complications in a cohort of 520 patients with liver transplantation. Perioperative mononeuropathy developed in 9 patients. The peroneal nerve, radial nerve, and cutaneous branch of the femoral nerve were affected in 2 patients each. Two patients had herpes zoster-associated radiculopathy, and 1 patient had Horner's syndrome. Recovery was good in most patients. In 7 patients, severe quadriplegia complicated the perioperative course. In 5 patients, electrophysiologic studies suggested acute necrotic myopathy, and muscle biopsy specimens showed evidence of rhabdomyolysis in 1 patient. Outcome in survivors was good, all recovering completely. We conclude that neuromuscular complications in liver transplantation are uncommon (less than 1%) and do not significantly contribute to morbidity. Mononeuropathies may have iatrogenic perioperative causes, and rhabdomyolysis may be an important cause of generalized muscle weakness after liver transplantation.

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.

Far-field auditory brainstem response in neurotologic surgery.

This is a review of our experience using far-field auditory brainstem monitoring during acoustic neuroma removal. The observations are based on 144 consecutive cases beginning in 1986. The factors of importance are tumor size, preoperative auditory function, and the preoperative presence of a wave V on the auditory brainstem response. Our experience suggests that preservation of hearing in tumors > 2.5 cm is rare. It was observed that preserving wave V does not guarantee preservation of hearing. Conversely, loss of wave V does not preclude preservation of hearing. It has also been noted that the presence of only wave I preoperatively does offer some hope that hearing can be preserved postoperatively. Finally, postoperative hearing function is usually equal to or worse than the preoperative function. Only rarely does the postoperative function improve.

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)

Electromyographic studies of the reconstructed lower eyelid after a modified Hughes procedure.

PURPOSE: We evaluated quantitatively, with electromyography, the function of orbicularis oculi muscle flaps in modified Hughes reconstructions of the lower eyelids. METHODS: A modified Hughes procedure with a bipedicle orbicularis oculi flap was used to reconstruct large left lower eyelid defects after tumor excision in six consecutive patients. Standard needle electromyography and facial nerve conduction studies were performed on each reconstructed lower eyelid, and results were compared with those of the unoperated-on right lower eyelid. Electromyographic studies were performed between 143 and 517 days after division of the tarsoconjunctival flap. RESULTS: Blink reflexes and results of facial nerve studies were normal and similar on both sides. All operated-on eyelids demonstrated electromyographic activity during voluntary orbicularis contraction. The functional and cosmetic results were satisfactory in all patients. No complications of reconstruction, such as eyelid retraction, ectropion, tissue necrosis, or abnormal contour or thickness, occurred. CONCLUSIONS: A modified Hughes procedure using a bipedicle orbicularis oculi flap provides viable, electrically active muscle to the reconstructed lower eyelid and may enhance the functional results.

The effect of botulinum toxin type A injection on compound muscle action potential in an in vivo rat model.

Serial measurements were performed on the compound muscle action potential (CMAP) amplitude and the force generated by the rat lower hind limb flexors to investigate the time course of intramuscular injections of botulinum toxin type A (BOTOX). Thirty animals were used in this in vivo rat model. CMAP amplitude and muscle force were measured at predetermined intervals for 28 weeks. Compound muscle action potential amplitude and force declined markedly the first 5 to 7 days after injection of BOTOX but recovered in a near linear manner. The response magnitude and recovery rate were dose-dependent. Recovery of CMAP amplitude preceded recovery of muscle force. No clear evidence of a systemic effect on the untreated leg or a concentration effect was found. CMAP amplitude may be useful in determining optimal timing of repeat injections in treating neuromuscular disorders.