Steven Orlov

Detection of Diabetic Sensorimotor Polyneuropathy by Corneal Confocal Microscopy in Type 1 Diabetes: A concurrent validity study

OBJECTIVE We aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics. RESEARCH DESIGN AND METHODS Concurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis. RESULTS DSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm2 (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm2, sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm2, specificity 93%, positive likelihood ratio 8.5). CONCLUSIONS Among CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.

Application of post-surgical stimulated thyroglobulin for radioiodine remnant ablation selection in low-risk papillary thyroid carcinoma.

We present our ongoing experience in the use of postsurgical stimulated serum thyroglobulin (Stim‐Tg) to assist in radioiodine remnant ablation (RRA) decision‐making.

Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes.

OBJECTIVE In vivo corneal confocal microscopy (IVCCM) has been proposed as a noninvasive technique to assess small nerve fiber structural morphology. We investigated the structure-function relationship of small fibers in diabetic sensorimotor polyneuropathy (DSP). RESEARCH DESIGN AND METHODS Ninety-six type 1 diabetic subjects with a spectrum of clinical DSP and 64 healthy volunteers underwent IVCCM examinations to determine corneal nerve structure, including corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and fiber tortuosity (CNFT). Small nerve fiber function was assessed by cooling detection thresholds (CDTs), axon reflex–mediated neurogenic vasodilatation in response to cutaneous heating by laser Doppler imaging flare technique (LDIFLARE), and heart rate variability (HRV). Linear associations between structural and functional measures in type 1 diabetic subjects were determined using Spearman correlation coefficients and linear regression analysis. RESULTS Of the type 1 diabetic subjects, with a mean age of 38.2 ± 15.5 years and a mean HbA1c of 7.9 ± 1.4%, 33 (34%) had DSP according to the consensus definition. Modest correlations were observed between CNFL, CNFD, and CNBD and all functional small-fiber tests (rs = 0.25 to 0.41; P ≤ 0.01 for all comparisons). For example, quantitatively every 1 mm/mm2 lower CNFL was associated with a 0.61°C lower CDT, a 0.07 cm2 lower LDIFLARE area, and a 1.78% lower HRV. No significant associations were observed for CNFT and the functional small-fiber measures. CONCLUSIONS Small nerve fiber structural morphology assessed by IVCCM correlated well with functional measures of small nerve fiber injury. In particular, CNFL, CNFD, and CNBD demonstrated clear structure-function relationships.

Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies.

CONTEXT Immunotherapies against immune checkpoints that inhibit T cell activation [cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1)] are emerging and promising treatments for several metastatic malignancies. However, the precise adverse effects of these therapies on thyroid gland function have not been well described. CASE DESCRIPTION We report on 10 cases of painless thyroiditis syndrome (PTS) from a novel etiology, following immunotherapy with anti-PD-1 monoclonal antibodies (mAb) during treatment for metastatic malignancies. Six patients presented with transient thyrotoxicosis in which thyrotropin binding inhibitory immunoglobulins (TBII) were absent for all, whereas four patients had evidence of positive antithyroid antibodies. All thyrotoxic patients required temporary beta-blocker therapy and had spontaneous resolution of thyrotoxicosis with subsequent hypothyroidism. Four patients presented with hypothyroidism without a detected preceding thyrotoxic phase, occurring 6-8 weeks after initial drug exposure. All of these patients had positive antithyroid antibodies and required thyroid hormone replacement therapy for a minimum of 6 months. CONCLUSIONS Patients receiving anti-PD-1 mAb therapy should be monitored for signs and symptoms of PTS which may require supportive treatment with beta-blockers or thyroid hormone replacement. The anti-PD-1 mAb is a novel exogenous cause of PTS and provides new insight into the possible perturbations of the immune network that may modulate the development of endogenous PTS, including cases of sporadic and postpartum thyroiditis.

INFLUENCE OF AGE AND PRIMARY TUMOR SIZE ON THE RISK FOR RESIDUAL/RECURRENT WELL-DIFFERENTIATED THYROID CARCINOMA

Though age and primary tumor size predict cancer‐specific survival in well‐differentiated thyroid carcinoma (WDTC), their influence on residual/recurrent disease has not been elucidated.

Predictive value of metastatic cervical lymph node ratio in papillary thyroid carcinoma recurrence.

The purpose of this study was to determine whether the proportion of metastatic cervical lymph nodes resected (metastatic lymph node ratio [MLNR]) predicted papillary thyroid carcinoma (PTC) recurrence, and whether MLNR could alter the predictive ability of TNM nodal classification for recurrence in PTC.

Heart Rate Variability and Sensorimotor Polyneuropathy in Type 1 Diabetes

OBJECTIVE Reduced heart rate variability (HRV) is classically viewed as an early phenomenon in diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the characteristics of HRV across the spectrum of clinical DSP in type 1 diabetes. RESEARCH DESIGN AND METHODS Eighty-nine diabetic subjects and 60 healthy volunteers underwent assessment of RR interval variation (RRvar) during deep breathing and clinical and electrophysiological examination. We examined the distribution of age-standardized RRvar across the spectrum of clinical DSP, identified variables associated with RRvar in multivariate regression, and compared RRvar with validated measures of neuropathy. RESULTS Age-standardized RRvar had a significant, step-wise, inverse relationship with ordinal categories of increasing DSP severity (β = −5.4, P < 0.0001) among subjects with diabetes. Case subjects with DSP had substantially lower age-standardized RRvar compared with diabetic control subjects without DSP (β = −5.2, P < 0.01), although there was substantial overlap of RRvar between diabetic case subjects and control subjects and the healthy volunteer cohort. In multivariate analysis, advanced age was independently associated with lower RRvar in both healthy volunteers and diabetic subjects, whereas higher glycated hemoglobin A1c and systolic blood pressure were independently associated with lower RRvar in diabetic subjects. RRvar had a significant association with validated measures of large and small fiber neuropathy. CONCLUSIONS HRV may be a biomarker for clinical DSP and is associated cross-sectionally with both early and late measures of neuropathy. The low HRV observed in some control subjects without DSP and in most case subjects with severe DSP may signify that HRV has different prognostic implications in these groups, requiring further longitudinal study.

PROGNOSTIC VALUE OF POSTSURGICAL STIMULATED THYROGLOBULIN LEVELS AFTER INITIAL RADIOACTIVE IODINE THERAPY IN WELL-DIFFERENTIATED THYROID CARCINOMA

In well‐differentiated thyroid carcinoma, predictors of future positivity of stimulated thyroglobulin (>2 μg/L) after initial radioactive iodine treatment are not known.

Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

BACKGROUND AND OBJECTIVES Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) <20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C <-3.3%/year) and incident advanced CKD (stage ≥3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] <60 ml/min per 1.73 m(2)). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards. RESULTS Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P<0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P<0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002). CONCLUSIONS Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.

The impact of common variation in the definition of diabetic sensorimotor polyneuropathy on the validity of corneal in vivo confocal microscopy in patients with type 1 diabetes: a brief report

The consensus definition for diabetic sensorimotor polyneuropathy allows for subtle variation in specific diagnostic criteria. In 89 type 1 diabetes participants, we found that common variations in these criteria do not impact the diagnostic validity of corneal nerve fiber length, a parameter of corneal in vivo confocal microscopy.