Follow up of MRI bone marrow edema in the treated diabetic Charcot foot - a review of patient charts.

Background: Ill-defined areas of water-like signal on bone magnetic resonance imaging (MRI), characterized as bone marrow edema or edema-equivalent signal-changes (EESC), is a hallmark of active-stage pedal neuro-osteoarthropathy (Charcot foot) in painless diabetic neuropathy, and is accompanied by local soft-tissue edema and hyperthermia. The longitudinal effects on EESC of treating the foot in a walking cast were elucidated by reviewing consecutive cases of a diabetic foot clinic. Study design: Retrospective observational study, chart review Material and methods: Cases with active-stage Charcot foot were considered, in whom written reports on baseline and follow-up MRI studies were available for assessment. Only cases without concomitant infection or skin ulcer were chosen, in whom both was documented, onset of symptomatic foot swelling and patient compliance with cast treatment. Results: From 1994 to 2017, 45 consecutive cases in 37 patients were retrieved, with 95 MRI follow-up studies (1-6 per case, average interval between studies 13 weeks). Decreasing EESC was documented in 66/95 (69%) follow-up studies. However, 29/95 (31%) studies revealed temporarily increasing, migrating or stagnating EESC. Conclusion: EESC on MRI disappear in response to prolonged offloading and immobilizing treatment; however, physiologic as well as pathologic fluctuations of posttraumatic EESC have to be considered when interpreting the MR images. Conventional MRI is useful for surveillance of active-stage Charcot foot recovery.

Conventional deep pressure algometry is not suitable for clinical assessment of nociception in painless diabetic neuropathy.

BACKGROUND: In diabetic persons with painless neuropathic foot ulceration, foot skin was found to be insensate to noxious pinprick stimulation (stimulation area less than 0.05 mm2), while compression of deep subcutaneous foot tissues by Algometer II® (stimulation area 1 cm2) could evoke a deep dull aching. To elucidate this discrepancy, the Algometer II stimulation technique was critically reviewed by varying probe sizes and anatomical sites in the same study population 3 years later. METHODS: Ten control subjects without neuropathy and 11 persons with painless diabetic neuropathy (PLDN, seven of whom with diabetic foot syndrome, i.e., past painless foot ulcer, or inactive Charcot arthropathy) were re-examined using Algometer II. Deep pressure pain perception threshold (DPPPT) was measured in random sequence with stimulation areas of 0.5 cm2, 1 cm2, and 2 cm2 (separated by 5 min intervals), at the plantar forefoot, the instep, and the hindfoot of both legs. RESULTS: In the control and PLDN groups, median DPPPTs differed significantly between stimulation areas (highest with 0.5 cm2, intermediate with 1 cm2, lowest with 2 cm2; p<0.001), and varied moderately by anatomical site. Between-group differences were relatively small. Results of the 1 cm2 assessments repeated 3 years apart were similar. CONCLUSIONS: Algometer II readings represent spatial summation of low-threshold pressure-receptor rather than of high-threshold nociceptor stimulation and are, thus, unhelpful for assessing PLDN. Reproducibility of the measurements is good.

Nociception at the diabetic foot, an uncharted territory.

The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy.

Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia) after acute foot trauma.

INTRODUCTION AND OBJECTIVE: Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic) neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy). DESIGN AND METHODS: A case-control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture). Cases were 12 patients (11 diabetic subjects) with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT) and deep pressure pain perception threshold (DPPPT) were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II(®)). RESULTS: In the control group, post-traumatic DPPPT (but not CPPPT) at the injured foot was reduced by about 15-25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15-20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal) versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group); CPPPT did not decrease post-operatively. CONCLUSION: Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic) neuropathy. A degree of post-traumatic hypersensitivity required to 'pull away' from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

Insulin-induced localized lipoatrophy preceded by shingles (herpes zoster): a case report.

INTRODUCTION: Localized involutional lipoatrophy of subcutaneous adipose tissue may develop due to subcutaneous injection of pharmaceutical preparations. The pathogenesis of this adverse drug reaction is unknown. The progression of localized involutional lipoatrophy ceases and occasionally it resolves after withdrawing the inducing agent. In case of localized involutional lipoatrophy due to subcutaneous insulin therapy, low-dose systemic corticosteroids may be curative despite ongoing insulin administration. CASE PRESENTATION: We report a recurrence of insulin-induced localized involutional lipoatrophy at the abdominal wall in a 57-year-old Caucasian woman with type-1 diabetes on continuous subcutaneous insulin infusion. The first episode of insulin-induced localized involutional lipoatrophy two years previously had been cured by oral prednisone. The recurrence was treated immediately with 10mg prednisone once daily for five months, and was cured thereafter. The insulin analog preparation (Humalog™) and the insulin pump equipment (Accu-Chek Spirit™) applied were the same during both episodes. Both episodes were preceded by a temporary disturbance of the immune balance (the first episode by vaccination, the second episode through shingles). CONCLUSIONS: This case confirms that insulin-induced localized involutional lipoatrophy in type-1 diabetes can occur again, and can be cured by systemic corticosteroids. We suggest that temporary disturbance of the immune balance may trigger this transitory idiosyncratic reaction in a susceptible individual.

The acute diabetic Charcot foot managed on the basis of magnetic resonance imaging--a review of 71 cases.

BACKGROUND: Acute Charcot foot (ACF) is a skeletal breakdown associated with inflammatory swelling of a foot in patients with pain insensitivity, such as diabetic neuropathy. In ACF stage 0, skeletal pathology (e.g. osseous oedema) is visible on magnetic resonance imaging (MRI), but not on plain radiographs. Continued unprotected walking invariably causes stage 1 (complex cortical fractures). Treatment by total contact cast (TCC) is of limited benefit if X-ray-based. The benefits of MRI-based TCC treatment are unknown. AIM: To assess the impact of MRI, all cases of ACF diagnosed by MRI between 2000 and 2012 were reviewed. METHOD: Audit of medical charts of a single outpatient diabetic foot clinic. RESULTS: Seventy-one cases (59 patients) were retrieved. Diagnosis of stage 0 (n = 27 cases) and stage 1 (n = 44 cases) was established one and two months (medians) after symptom onset, respectively. Unremarkable radiographs, that were not cross-checked by MRI (n = 13 cases), misled primary care physicians to postpone referral until five months after symptom onset, when cortical fractures had already occurred in 12 cases. Midfoot (Chopart- and Lisfranc-) lesions healed better in stage 0 versus stage 1 (69% versus 7% without deformities, p = 0.0012), while forefoot (metatarsal) lesions healed well in either stage (100% versus 75% without deformities). TCC-treatment lasted four to six months. CONCLUSION: Healing of ACF was more efficient in stage 0 than in stage 1. Expeditious MR imaging was indispensable to diagnose stage 0 in a swollen foot of a neuropathic patient, while unremarkable X-rays often led to a missed diagnosis.

Pressure pain perception in the diabetic Charcot foot: facts and hypotheses.

BACKGROUND: Reduced traumatic and posttraumatic (nociceptive) pain is a key feature of diabetic neuropathy. Underlying condition is a gradual degeneration of endings of pain nerves (A-delta fibers and C-fibers), which operate as receivers of noxious stimuli (nociceptors). Hence, the absence of A-delta fiber mediated sharp pain ("first" pain), and of C-fiber mediated dull pain ("second" pain). However, patients with diabetic neuropathy and acute Charcot foot often experience deep dull aching in the Charcot foot while walking on it. AIM: To create a unifying hypothesis on the kind of pain in an acute Charcot foot. RESULT: Absence of punctuate (pinprick) pain perception at the sole of a Charcot foot, as was shown recently, likely corresponds to vanished intraepidermal A-delta fiber endings. C-fiber nociceptors are reduced, according to histopathology studies. Both types of fibers contribute to posttraumatic hyperalgesia at the skin level, as studies show. Their deficiencies likely impact on posttraumatic hyperalgesia at the skin level and, probably, also at the skeletal level. CONCLUSION: It is hypothesised that deep dull aching in an acute diabetic Charcot foot may represent faulty posttraumatic hyperalgesia involving cutaneous and skeletal tissues.

The diagnostic value of measuring pressure pain perception in patients with diabetes mellitus.

QUESTION UNDER STUDY: Repetitive skin trauma and reduced pressure pain sensation are necessary components of plantar ulcer risk in patients with diabetic neuropathy. The diagnostic value of measuring pressure nociception to detect ulcer risk is, however, unknown. Instead, measuring the vibration perception threshold (VPT) by 64 Hz graduated Rydel-Seiffer tuning fork has become standard clinical practice to screen for neuropathy and ulcer proneness. We therefore set up a diagnostic case-control study to compare the VPT, the cutaneous pressure pain perception threshold (CPPPT) and the deep pressure pain perception threshold (DPPPT) at the foot sole in diabetic patients with and without past or present painless plantar ulcer. METHODS: A total of 68 patients were studied, 34 with active or previous plantar ulcer. VPT was measured by Rydel-Seiffer tuning fork at the 1st metatarsal head (≤4/8 grade indicating clinical neuropathy). CPPPT was measured at a toe skinfold by calibrated monofilaments. DPPPT was measured by Algometer II(®) over musculus hallucis longus and over a metatarsophalangeal joint. RESULTS: The sensitivity and specificity to identify patients with present or past foot ulcer were as follows: 0.82 and 0.88 (VPT cut-off 1/8); 0.97 and 0.62(VPT cut-off 4/8); 0.93 and 0.77 (CPPPT cut-off 513 mN); 0.76 and 0.58 (DPPPT muscle, cut-off 545 kPa); 0.82 and 0.79 (DPPPT joint, cut-off 760 kPa). CONCLUSION: Pressure algometry was not superior to measuring VPT for distinguishing between patients with and without painless plantar ulcers; VPT ≤1/8 was more efficient than ≤4/8 grade in identifying ulcer patients.

Relapsing insulin-induced lipoatrophy, cured by prolonged low-dose oral prednisone: a case report.

INTRODUCTION: Circumscript, progressing lipoatrophy at the insulin injection sites is an unexplained, however rare condition in diabetes mellitus. CASE PRESENTATION: We report a case of severe localised lipoatrophy developing during insulin pump-treatment (continuous subcutaneous insulin infusion) with the insulin analogue lispro (Humalog®) in a woman with type-1 diabetes mellitus. After 11 months of progressing lipoatrophy at two spots on the abdomen, low-dose prednisone (5-10 mg) p.o. was given at breakfast for 8 months, whereby the atrophic lesions centripetally re-filled with subcutaneous fat tissue (confirmed by MRI) despite ongoing use of insulin lispro. However, 4 weeks after cessation of prednisone, lipoatrophy relapsed, but resolved after another 2 months of low-dose prednisone. No further relapse was noted during 12 months of follow-up on insulin-pump therapy with Humalog®. CONCLUSION: Consistent with an assumed inflammatory nature of the condition, low-dose oral prednisone appeared to have cured the lipoatrophic reaction in our patient. Our observation suggests a temporary intolerance of the subcutaneous fat tissue to insulin lispro (Humalog®), triggered by an unknown endogenous mechanism.

Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years.

In order to provide comprehensive information on the differences in bioactivity between human insulin and insulin analogues, published in vitro comparisons of human insulin and the rapid acting analogues insulin lispro (Humalog®), insulin aspart ( NovoRapid®), insulin glulisine (Apidra®), and the slow acting analogues insulin glargine (Lantus®), and insulin detemir (Levemir®) were gathered from the past 20 years (except for receptor binding studies). A total of 50 reports were retrieved, with great heterogeneity among study methodology. However, various differences in bioactivity compared to human insulin were obvious (e.g. differences in effects on metabolism, mitogenesis, apoptosis, intracellular signalling, thrombocyte function, protein degradation). Whether or not these differences have clinical bearings (and among which patient populations) remains to be determined.

Sudeck's disease stage 1, or diabetic Charcot's foot stage 0? Case report and assessment of the diagnostic value of MRI.

BACKGROUND: The diagnosis of Sudeck's syndrome stage 1 (nowadays termed complex regional pain syndrome I, abbreviated CRPS I) is based on clinical features, namely swelling and pain in a limb. Plain X-ray may be normal. In the absence of pain sensitivity, e.g. in diabetic neuropathy, CRPS I of the foot can be mistaken for Charcot's foot stage 0 (so-called neuro-osteoarthropathy). CASE PRESENTATION: The case of a type-1 diabetic woman is reported, in whom CRPS I following a calcaneal fracture was mistaken for Charcot's osteoarthropathy (because of bone marrow edema displayed by conventional MR imaging). In addition, a review is presented on 6 consecutive cases with CRPS I of the foot, and on 20 cases with Charcot's foot stage 0, with particular emphasis on MR imaging findings. The number of bones per foot affected with marrow edema was similar in either condition, with a tendency towards a more patchy, diffuse distribution of bone marrow edema in CRPS I. Bone marrow edema apparently regressed more promptly in response to treatment in Charcot's foot stage 0. CONCLUSION: Differentiation of CRPS I from Charcot's foot stage 0 remains a diagnostic dilemma in patients with pain insensitivity. Conventional MRI may be helpful, when repeated for monitoring the treatment response.

Routine MRI findings of the asymptomatic foot in diabetic patients with unilateral Charcot foot.

BACKGROUND: Imaging studies of bones in patients with sensory deficits are scarce. AIM: To investigate bone MR images of the lower limb in diabetic patients with severe sensory polyneuropathy, and in control subjects without sensory deficits. METHODS: Routine T1 weighted and T2-fat-suppressed-STIR-sequences without contrast media were performed of the asymptomatic foot in 10 diabetic patients with polyneuropathy and unilateral inactive Charcot foot, and in 10 matched and 10 younger, non-obese unmatched control subjects. Simultaneously, a Gadolinium containing phantom was also assessed for reference. T1 weighted signal intensity (SI) was recorded at representative regions of interest at the peritendineal soft tissue, the tibia, the calcaneus, and at the phantom. Any abnormal skeletal morphology was also recorded. RESULTS: Mean SI at the soft tissue, the calcaneus, and the tibia, respectively, was 105%, 105% and 84% of that at the phantom in the matched and unmatched control subjects, compared to 102% (soft tissue), 112% (calcaneus) and 64% (tibia) in the patients; differences of tibia vs. calcaneus or soft tissue were highly significant (p < 0.005). SI at the tibia was lower in the patients than in control subjects (p < 0.05). Occult traumatic skeletal lesions were found in 8 of the 10 asymptomatic diabetic feet (none in the control feet). CONCLUSION: MR imaging did not reveal grossly abnormal bone marrow signalling in the limbs with severe sensory polyneuropathy, but occult sequelae of previous traumatic injuries.