Prevention of axonal loss after immediate dosage titration of immunoglobulin in multifocal motor neuropathy.

BACKGROUND: To evaluate whether ongoing axonal loss can be prevented in multifocal motor neuropathy (MMN) treated with immunoglobulin G (IgG), a group of patients with a median disease duration of 15.7 years (range: 8.3-37.8), treated with titrated dosages of immunoglobulins, was studied electrophysiologically at time of diagnosis and at follow-up. RESULTS: At follow-up, the Z-score of the compound motor action potential amplitude of the median, fibular, and tibial nerves and the neurological performances were determined. In seven patients with a treatment-free period of 0.3 years (0.2-0.4), there was no progression of axonal loss (p = 0.2), whereas a trend toward further axonal loss by 1.3 Z-scores (0.9-17.0, p = 0.06) was observed in five patients with a treatment-free period of 4.0 years (0.9-9.0). The axonal loss in the group with a short treatment delay was significantly smaller than in the group with a longer treatment delay (p = 0.02). Also, there was an association between treatment delay and ongoing axonal loss (p = 0.004). The electrophysiological findings at follow-up were associated with the isokinetic strength performance, the neurological impairment score, and the disability, supporting the clinical relevance of the electrophysiological estimate of axonal loss. CONCLUSION: Swift initiation of an immediately titrated IgG dosage can prevent further axonal loss and disability in continuously treated MMN patients.

Outcome in chronic inflammatory demyelinating polyneuropathy: A systematic review and meta-analysis.

INTRODUCTION/AIMS: Outcomes in chronic inflammatory demyelinating polyneuropathy (CIDP) have been reported in longitudinal and cross-sectional studies. A considerable variation in long-term disease outcome has appeared in those reports. To overcome this uncertainty, a systematic review and meta-analysis was conducted on CIDP outcomes, including the parameters of case fatality rate, ambulation, physical ability, and remission. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search was conducted in PubMed and EMBASE (OVID) for reports with at least 2 years of follow-up on patients with active or previously active CIDP that were published no later than May 12, 2022. Studies were appraised for quality using the Joanna Briggs Institute Critical Appraisal Checklist for studies reporting prevalence data. Pooled analyses were conducted and the results were visualized using forest plots. The study protocol was registered prospectively on PROSPERO (CRD42021266903). RESULTS: A total of 1290 titles were identified. Sixty-nine full-text articles were screened and 21 studies with 1199 patients were selected for the data analysis. The pooled case fatality rate was 3.3% (95% confidence interval [CI], 1.9% to 5.7%). The pooled fraction of nonambulatory patients was 8.2% (95% CI, 5.7% to 11.6%) and, overall, 47.1% (95% CI, 39.5% to 54.9%) of CIDP patients had a good outcome without disability. The pooled rate of remission was 40.8% (95% CI, 30.6% to 51.8%). DISCUSSION: Future research is warranted on how to prevent long-term impairment in CIDP. Care should be taken in developing clinical strategies to avoid immunomodulating therapy in the many patients in remission.

Axonal loss at time of diagnosis as biomarker for long-term disability in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: We hypothesized that early, pretreatment axonal loss would predict long-term disability, supported by a pilot study of selected patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To further test this hypothesis, we examined a larger consecutive group of CIDP patients. METHODS: Needle electromyography and motor and sensory nerve conduction studies were carried out in 30 CIDP patients at pretreatment and follow-up 5 to 28 years later. Changes in amplitudes were expressed as axonal Z scores and changes in conduction as demyelination Z scores and correlated with findings of the Inflammatory Rasch-built Overall Disability Scale (I-RODS), the Neuropathy Impairment Score (NIS), and isokinetic dynamometry (IKS). RESULTS: At follow-up, the median I-RODS score was 73, the NIS was 23, and the IKS was 56%. The median axonal Z score was unchanged at follow-up. Conversely, the corresponding demyelination Z scores improved. The initial axonal loss was correlated with the clinical outcome and was an independent predictor of outcome by multivariate regression analysis. Axonal loss at follow-up was also correlated with the clinical outcome. Only the follow-up demyelination Z score was correlated with the clinical outcomes. Furthermore, the latency until treatment initiation was predictive of all three clinical outcome scores at follow-up, and of axonal loss and demyelination at follow-up. DISCUSSION: The present study findings indicate that pretreatment axonal loss at diagnosis in CIDP is predictive of long-term disability, neurological impairment, and strength. A delay in treatment is associated with more pronounced axonal loss and a worse clinical outcome.

A population-based study of long-term outcome in treated chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: The effect of long-lasting immune-modulating therapy was studied in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: A population-based, cross-sectional study of treated patients referred to the Danish health-care system between 1985 and 2006. RESULTS: The 51 participating patients had a median disease duration of 16 (interquartile range, 14-21) years. Twenty-seven patients (53%) had discontinued therapy and 46 walked independently. Disability and isokinetic strength were impaired by 17% and 20%, respectively, as compared with matched control subjects. For a few patients long-term CIDP was associated with severe morbidity (6%) and even mortality (1%). Prolongation of time until start of therapy was associated with an increased burden of long-term disability. DISCUSSION: Long-term prognosis in treated CIDP is characterized by limited disability in the majority of patients. Disability is related to delay of therapy. Therefore, more attention should be given to early treatment start in CIDP.

Muscle weakness and functional disability in patients with myasthenia gravis.

INTRODUCTION: Muscle weakness and functional disability have not been evaluated in a population-based study of patients with myasthenia gravis (MG). METHODS: All patients with MG in a well-defined catchment area were identified in the Danish National Patient Registry. Of the 175 eligible patients, 90 participated and were studied using MG-specific scales, isometric dynamometry, and functional tests. Fifty age- and sex-matched subjects served as controls. RESULTS: Muscle strength was reduced by 13%, 21%, and 12% for shoulder abduction, knee extension, and ankle extension, respectively (P < 0.05). Chair stand and 400-meter walking were impaired by 24% and 23%, respectively (P < 0.05). Muscle strength and functional performances were related to MG-specific scales. DISCUSSION: MG patients have moderately reduced isometric muscle strength and impaired physical performance. Muscle weakness and functional tests relate closely to MG-specific scales, suggesting that dynamometry and functional tests can be used to monitor MG patients and as efficacy parameters in clinical trials. Muscle Nerve 59:218-223, 2019.

A population-based and cross-sectional study of the long-term prognosis in multifocal motor neuropathy.

A population-based, cross-sectional study of patients referred to the Danish hospital system between 1985 and 2006 was conducted to evaluate the long-term outcome in Danish patients treated for multifocal motor neuropathy (MMN). Thirty-four MMN patients were identified, three had died of unrelated diseases, 10 were excluded, one did not reply to study request and 20 were included. The median disease duration was 24 years (interquartile range: 18.5-31.0). Compared to 24 healthy matched control subjects, the Rasch-built Overall Disability Scale for Multifocal Motor Neuropathy was reduced by 9%, the Neuropathy Impairment Score showed a 3-fold increase, the isokinetic strength was reduced by 29%, the grip strength by 56%, the Timed 25-Foot Walk was prolonged by 13% and the EQ-5D-5 L-Index value was impaired by 20%. The isokinetic strength was significantly more impaired at the wrist and ankle as compared to the elbow and knee, and one patient had lost ambulation because of instability at the ankle. Patients were considerably more fatigued and had substantially impaired hand dexterity, while mood, aerobic capacity, social adjustment, and working capacity were not affected. Regression analysis showed that lag-time until start of initial therapy lead to impaired long-term outcome without any effect of disease duration. Long-term prognosis in treated MMN is characterized by moderate to severe impairment primarily affecting dexterity and stability at the ankle. Our observations support previous observations that the long-term impairment in MMN might be improved following earlier start of therapy and that an effect of disease duration cannot be demonstrated.

Comparisons in fluctuation of muscle strength and function in patients with immune-mediated neuropathy treated with intravenous versus subcutaneous immunoglobulin.

INTRODUCTION: Variations in muscle strength and function have not been studied in patients with chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy whose treatment regimen has been changed from intravenous to subcutaneous immunoglobulin (IVIg to SCIg). METHODS: In a prospective, open-label study, patients were changed from monthly IVIg to weekly SCIg. The primary endpoint was variation in isokinetic muscle strength (cIKS). Secondary endpoints were variations in Medical Research Council (MRC) score, grip strength (GS), 9-hole-peg test (9-HPT), and 40-meter-walk test (40-MWT). RESULTS: The coefficient of variance of cIKS during the IVIg and SCIg treatment periods was unchanged (mean ± SD: 6.97 ± 4.83% vs. 5.50 ± 3.13%, P = 0.21). The variations in the 9-HPT and 40-MWT were significantly lower in the SCIg group (P = 0.01 and P = 0.005, respectively). DISCUSSION: When therapy was changed from IVIg to SCIg, fluctuation of muscle strength was unchanged, but performance fluctuations were diminished. Muscle Nerve 57: 610-614, 2018.

Improvement of hemoglobin levels after a switch from intravenous to subcutaneous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy.

BACKGROUND: Intravenous immunoglobulin (IVIG) is recommended treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Recent studies have demonstrated that subcutaneous immunoglobulin (SCIG) is feasible, safe, and effective in both disorders. IVIG leads to transient hemolysis and, consequently, we hypothesized that frequent small doses of SCIG exerts less hemolytic activity than a few larger doses of IVIG. STUDY DESIGN AND METHODS: In an open-label study, 23 three patients treated with IVIG for CIDP or MMN were switched to SCIG at an equal dosage. IVIG was administered two to three times for 6 weeks. Two weeks after the last IVIG infusion at Week 8, SCIG was initiated with injections twice or thrice weekly until Week 20. Blood samples were drawn 2 weeks after IVIG at Weeks 2 and 8 and during SCIG at Weeks 14 and 20 determining hemoglobin (Hb) and hemolytic variables. RESULTS: Seventeen patients completed the study. At enrollment, the Hb level was 138 ± 12 g/L, haptoglobin level was 1.4 ± 0.5 g/L, reticulocyte count was 58.7 × 109  ± 21.3 × 109 /L, and bilirubin level was 6.6 ± 2.3 µmol/L. The average of the two blood samples drawn at comparable intervals during IVIG and SCIG showed that Hb increased from 135 ± 15 to 138 ± 15 g/L (p = 0.03). During IVIG the hemolytic variables showed signs of mild hemolysis that improved during SCIG, haptoglobin increasing from 1.2 ± 0.5 to 1.5 ± 0.6 g/L (p = 0.002), reticulocytes decreasing from 71.9 × 109  ± 35.8 × 109 to 54.5 × 109  ± 16.3 × 109 /L (p = 0.02), and bilirubin decreasing from 7.3 ± 2.8 to 5.8 ± 1.8 µmol/L (p = 0.001). CONCLUSION: A switch from IVIG to SCIG was associated with a slight increase of Hb levels and an improvement of laboratory variables related to hemolytic activity.

Diurnal and day-to-day variation of isometric muscle strength in myasthenia gravis.

INTRODUCTION: In patients with myasthenia gravis (MG), muscle strength is expected to decrease gradually during the day due to physical activities. METHODS: Isometric muscle strength at the shoulder, knee, and ankle was determined in 10 MG patients (MGFA class II-IV) who were receiving usual medical treatment and in 10 control subjects. To determine diurnal and day-to-day variation, muscle strength was measured 4 times during day 1 and once at day 2. RESULTS: Knee extension strength decreased during the day in both patients and controls. Neither diurnal nor day-to-day variation of muscle strength was higher in patients compared with controls. CONCLUSIONS: Patients with mild to moderate MG did not have increased variation of isometric muscle strength during the day or from day-to-day compared with controls. This suggests that isometric muscle performance can be determined with high reproducibility in similar groups of MG patients without regard to time of day.

Skeletal muscle fiber characteristics and oxidative capacity in hemiparetic stroke survivors.

INTRODUCTION: Skeletal muscle is changed after stroke, but conflicting data exist concerning muscle morphology and oxidative enzyme capacity. METHODS: In 36 chronic stroke patients bilateral rectus femoris muscle biopsies were analyzed, and fiber type proportions and cross-sectional areas were determined by ATPase histochemistry. Enzymatic concentrations of citrate synthase (CS) and 3-Hydroxyacyl-coenzymeA-dehydrogenase (HAD) were determined using freeze-dried muscle tissue. Findings were correlated with clinical outcomes. RESULTS: In the paretic muscles the mean fiber area was smaller (P = 0.0004), and a lower proportion of type 1 fibers (P = 0.0016) and a higher proportion of type 2X fibers (P = 0.0002) were observed. The paretic muscle had lower CS (P = 0.013) and HAD concentrations (P = 0.037). Mean fiber area correlated with muscle strength (r = 0.43; P = 0.041), and CS concentration correlated with aerobic capacity (r = 0.47; P = 0.01). CONCLUSIONS: In stroke survivors there is a phenotypic shift toward more fatigable muscle fibers with reduced oxidative enzymatic capacity that relates to clinical outcomes.

Mortality in myasthenia gravis: A nationwide population-based follow-up study in Denmark.

INTRODUCTION: In previous studies of myasthenia gravis (MG), increased mortality has been reported. The aim of this study was to estimate mortality in patients with acetylcholine receptor antibody-positive (AChR-Ab-seropositive) MG in a nationwide population-based, long-term follow-up study. METHODS: All AChR-Ab-seropositive MG patients, diagnosed between 1985 and 2005, were identified. Defined by age at diagnosis (≤ 50 or >50 years), patients were classified as having early- or late-onset MG. For comparison, 10 non-MG individuals from the general population were matched with each patient. All patients and controls were followed until January 1, 2009. Mortality rates and estimated mortality rate ratios (MRRs) were calculated. RESULTS: Of 702 AChR-Ab-seropositive MG patients, 302 died during follow-up. Overall mortality was higher for patients with MG (MRR = 1.41, range 1.24-1.60). In late-onset women and men, the MRRs were 1.64 (1.36-1.99) and 1.22 (1.02-1.46), respectively. Total MRR was highest during the first 5 years after diagnosis. CONCLUSIONS: MG diagnosis is still associated with increased mortality.

Upper Respiratory Infections and MRI Activity in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Although clinical reports have suggested a relationship between systemic infections and multiple sclerosis (MS) relapses, MRI evidence supporting an association is conflicting. Here we evaluated the temporal relationship between upper respiratory infections (URIs) and MRI activity in relapsing-remitting (RR) MS. METHODS: We combined individual data on URI with data on active lesions in pre-scheduled MRI examinations performed every 4 weeks for 28 weeks in 69 patients. A 4-week at-risk (AR) period started, by definition, 1 week before the onset of a URI. We recorded the relationship between the number of active lesions in each MRI with (1) the number of days of AR time in the immediately preceding 4-week period and (2) the number of days passed since the onset of a preceding URI. RESULTS: Average MRI lesions/day showed no difference between AR (0.0764) and not-AR (0.0774) periods. The number of lesions in 483 pre-scheduled MRI examinations did not correlate with the AR proportion in the prior 4-week period (rho = -0.03), and time from URI onset did not correlate with lesion number on the next MRI examination (rho = 0.003). CONCLUSION: The occurrence of a URI did not increase the risk of MRI activity evaluated in an adjacent 4-week window in RRMS.

Cerebellar ataxia-neuropathy-vestibular areflexia-syndrome.

CANVAS including its clinical components of cerebellar ataxia, sensory neuropathy and vestibular areflexia is presented in this review. An intronic biallelic pentanucleotide expansion in RFC1 is the genetic cause of CANVAS. Several patients diagnosed with isolated "idiopathic" neurological or otological conditions might have a CANVAS spectrum disorder. The number of CANVAS patients may well increase considerably in the near future, making it important to consider the diagnostic set-up and infrastructure for counselling, treatment and follow-up in the Danish healthcare system.

Normalized muscle strength, aerobic capacity, and walking performance in chronic stroke: a population-based study on the potential for endurance and resistance training.

OBJECTIVES: To assess muscle strength, aerobic capacity, and walking performance compared with normative values in chronic hemiparetic stroke patients and, thereby, to investigate the potential for endurance and resistance training. Second, to study the relations between muscle strength, aerobic capacity, and walking performance using normalized test values. DESIGN: Population-based, cross-sectional study. SETTING: University hospital, outpatient clinic. PARTICIPANTS: Patients (N=48) aged 50 to 80 years with reduced muscle strength and walking capacity due to an ischemic stroke 6 to 36 months prior to recruitment. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Peak oxygen consumption (Vo(2)peak) and isometric knee extensor muscle strength at the paretic knee were expressed as absolute and normalized values using normative data. The six-minute walk test (6MWT) and the habitual ten-meter walk test (10MWT) were secondary parameters. RESULTS: Peak Vo(2) was 77% (95% confidence interval [CI], 71-84) of the expected value, and the strength of the paretic knee was 71% (95% CI, 64-78), whereas walking speed (10MWT) was 59% (95% CI, 52-66) and walking distance (6MWT) was 59% (95% CI, 52-67). The normalized Vo(2)peak correlated to the normalized 6MWT (r=.58; P<.001) and normalized 10MWT (r=.53; P<.001). Normalized strength of the paretic knee correlated to normalized 6MWT (r=.40; P<.01) and normalized 10MWT (r=.31; P<.05). CONCLUSIONS: Lower extremity muscle strength and aerobic capacity are related to walking performance, which suggests a potential for endurance and resistance training in rehabilitation of walking performance in chronic hemiparesis after stroke. Correction for the influence of age, weight, and height providing normalized values improves the interpretation of severity of impairments and enables comparisons between patients.

Long-term follow-up of facilitated subcutaneous immunoglobulin therapy in multifocal motor neuropathy.

OBJECTIVE: To assess the feasibility, efficacy and patient satisfaction of long-term facilitated subcutaneous immunoglobulin therapy (fSCIG) in multifocal motor neuropathy (MMN). METHODS: Twelve patients previously participating in a randomized trial investigating the short-term efficacy of fSCIG were offered to switch to fSCIG maintenance therapy following a variable interval on conventional subcutaneous immunoglobulin. RESULTS: Eight patients were switched to fSCIG maintenance therapy, seven of whom were invited for a follow-up assessment after 18 months (range 13-23 months) of treatment. The age at follow-up was 57 years (range 45-70 years) and patients received a median weekly dose immunoglobulin G of 32.5 g (range 20.0-50.0 g), the dose being unaltered compared to baseline values following completion of the fSCIG trial. In five patients the infusion was biweekly, whereas two patients were infused weekly. The follow-up mean isometric strength normalized to pre-trial values was 107.7% (95% CI 86.4-129.0%) being non-inferior to baseline values (104.7%, 95% CI 97.6-111.8%, P = 0.015). The mean ODSS was 2.0 (95% CI 0.8-3.2) which is identical to the baseline score following completion of the fSCIG trial, the P-value for non-inferiority being <0.0001. The secondary variables of impairment, function and quality of life at follow-up all were non-inferior to baseline values (P ≤ 0.046). CONCLUSION: fSCIG seems feasible and effective for long-term maintenance treatment in patients with MMN.

Early axonal loss predicts long-term disability in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To investigate early pre-treatment nerve fiber loss as a predictor of long-term clinical outcome in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: In 14 patients, motor and sensory conduction studies of the median, fibular, and sural nerves were performed at pre-treatment and follow-up 11-28 years later. Z-scores of amplitudes were combined as biomarkers of axonal loss and Z-scores of conduction properties as demyelination scores. The axonal loss was further examined by electromyography (EMG) and motor unit number estimation. Axonal and demyelination scores were compared to clinical outcomes in the Inflammatory Rasch-built Overall Disability Scale, the Neuropathy Impairment Score, and dynamometry. RESULTS: At follow-up 12 patients walked independently, one needed support and one could not walk. The initial and follow-up axonal and demyelination scores were markedly abnormal. The initial axonal loss but not demyelination was strongly associated with both the follow-up axonal loss and the clinical measures. Moreover, delay of treatment initiation negatively influenced the axonal scores and clinical outcomes. CONCLUSION: In this hypothesis generating limited study, we found that axonal loss at early CIDP was highly predictive for long-term nerve fiber loss and disability. SIGNIFICANCE: The study indicates that prompt initiation of treatment to prevent nerve fiber loss is necessary for outcome in CIDP.

Cortical excitability in chronic stroke and modulation by training: a TMS study.

BACKGROUND: A possible role for GABA in regulating cortical plasticity after stroke has been proposed. OBJECTIVE: To investigate changes in intracortical inhibitory and facilitatory circuits in the affected hemisphere more than 6 months after stroke, as well as modulation of excitability by a single training session. METHODS: A total of 22 patients >6 months after stroke were compared to age- and gender-matched healthy participants. Cortical excitability was assessed by transcranial magnetic stimulation (TMS), including paired-pulse stimulation, before and up to 30 minutes after a single 15-minute session of 1 Hz thumb abduction-adduction movements. RESULTS: At baseline, TMS showed decreased intracortical inhibition in the affected hemisphere of patients (P = .004) compared to healthy participants. After training a short-lasting decline in motor evoked potentials was observed in both patients (P = .002) and healthy participants (P = .06). Moreover, in healthy participants, inhibitory activity decreased up to 30 minutes after training whereas no significant change was seen in the patients. CONCLUSIONS: The findings indicate that inhibitory intracortical circuits are less active after stroke, and no change in inhibitory activity is evident after a single training session. This may indicate that intracortical disinhibition is beneficial during recovery and that an impaired capacity for modulation remains in the chronic stage of stroke.

[Chronic inflammatory demyelinating polyneuropathy].

In this review, we discuss chronic inflammatory demyelinating polyneuropathy (CIDP), which is a disease with proximal and distal weakness and sensory disturbances resulting in impaired daily activity. The diagnosis is based on the clinical presentation and electrophysiology demonstrating demyelination in the peripheral nerves. CIDP can be successfully treated with immunoglobulin, glucocorticoids or plasma exchange, and during the latest decade, immunoglobulin has been administered subcutaneously improving patients' flexibility and autonomy. By time, 30% of the patients will remit, and maintenance treatment will no longer be necessary.

Muscle performance relates to physical function and quality of life in long-term chronic inflammatory demyelinating polyradiculoneuropathy.

The aim of the present study was to determine the severity and distribution of assessed muscle weakness and to relate muscle performance to measures of function and quality of life in long-term chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Fourteen patients with 8.7 years (3.3-11.5) of confirmed CIDP consecutively referred to the referral center for CIDP patients at Aarhus University Hospital, Denmark, during the period 1992-2002 were compared with matched healthy controls. The main outcome parameter was muscle performance assessed with isokinetic dynamometry. Overall disability sum score (ODSS), neurological symptom score (NSS), neuropathy impairment score (NIS), health-related quality-of-life survey (SF-36), nerve conduction studies, physical fitness, hand and walking performance, and quantitative sensory testing were secondary variables. The mean (95% CI) isokinetic strength of all measured muscles was reduced by 19.4% (5.9-32.8%) (p < 0.01). In the legs, distal weakness was predominant, strength at ankle being 37.0% (14.7-59.2%) reduced. Isokinetic strength was closely related to manual muscle strength, ODSS, NIS, walking performance, and physical components of SF-36. In conclusion, isokinetic strength relates to measures of function, impairments, gait performance, and physical components of health-related quality of life in long-term CIDP. Furthermore, a detailed characterization of severity and distribution of weakness has been provided using this technique.

Muscle weakness: a progressive late complication in diabetic distal symmetric polyneuropathy.

The aim of the study was to determine the progression of muscle weakness in long-term diabetes and its relation to the neuropathic condition. Thirty patients were recruited from a cohort of 92 diabetic patients who participated in a study on muscular function 6-8 years earlier. Nine subjects were nonneuropathic, 9 had asymptomatic neuropathy, and 12 had symptomatic neuropathy. Thirty matched control subjects who participated in the initial studies were also included. At follow-up, isokinetic dynamometry at the ankle, electrophysiological studies, vibratory perception thresholds, and clinical examination (neuropathy symptom score and neurological disability score [NDS]) were repeated. The annual decline of strength at the ankle was 0.7 +/- 1.7% in control subjects, 0.9 +/- 1.9% in nonneuropathic patients, 0.7 +/- 3.1% in asymptomatic neuropathic patients, and 3.2 +/- 2.3% in symptomatic neuropathic patients. In the symptomatic patients, the decline of muscle strength at the ankle was significant when compared with matched control subjects (P = 0.002) and with the other diabetic groups (P = 0.023). Also, the annual decline of muscle strength at the ankle was related to the combined score of all measures of neuropathy (r = -0.42, P = 0.03) and to the NDS (r = -0.52, P = 0.01). In patients with symptomatic diabetic neuropathy, weakness of ankle plantar and dorsal flexors is progressive and related to the severity of neuropathy.