Long-standing Neuropathy Research Articles

Polyarthritis, neuropathy, and persistent violaceous plaques

A 77-year-old woman from India presented with a rash of 2 months' duration, long-standing neuropathy in a stocking glove distribution, polyarthritis, and fever. The cutaneous eruption consisted of violaceous-to-erythematous patches, nodules, and plaques with associated edema, starting on the bilateral hands and feet and gradually spreading to the proximal limbs, trunk and face (Fig 1, A). The patient had lived in the United States for 2 decades and last visited India 2 years ago. Laboratory tests were remarkable for anti-nuclear antibody positivity, elevated C-reactive protein and erythrocyte sedimentation rate, and slightly decreased complement C3.

Novel Pathology Classification System (FEMASK-Score) for Charcot Neuropathic Arthropathy Reveals Intraneural Vasculopathy and Predicts Outcome

Category:Basic Sciences/Biologics; Ankle; Diabetes; Midfoot/ForefootIntroduction/Purpose:Charcot neuropathic arthropathy (CNA) is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for CNA previously relied on Eichenholtz Stage. There is limited data on CNA histopathology. The goal of this study was to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy.Methods:Retrieval of surgical pathology specimens from neuroarthropathic CNA patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large to small periarticular bone fragments to resolution, we devised and applied a CNA FEMASK-score (named after coauthors): 0= intraneural arteriolosclerosis; 1= large bone fragments without host histiocytic response; 2= mixed bone fragments with host histiocytic response; 3= small minute bone spicules resorption to fibrosis. Clinical modified Eichenholtz staging and outcome were then compared the CNA FEMASK-score to assess for associations between these three elements.Results:Forty-eight cases of CNA included 34 males and 14 females, mean age 60.3 and age range 28-83 years, with clinical diabetes mellitus (predominantly Type II) and longstanding neuropathy. Elevated HbA1C, Eichenholtz stage, American Society of Anesthesia score, and Charlson comorbidity index were predictive of amputation. Pathologic specimens varied from fixation tissue to amputation. In addition to neurotraumatic, neurovascular and inflammatory findings, a distinctive intraneural hyalinized arteriolosclerosis was observed. FEMASK-scores:1 = 10%, 2= 58%, and 3=32%. FEMASK-score comparisons were 98% accurate compared with the modified Eichenholtz criteria scores of each patient and 98% reproducible among pathologists. FEMASK 2 and 3 correlates strongly with amputation.Conclusion:Our novel CNA FEMASK-score classification, derived from the largest cohort of diabetic neuropathic specimens, is reproducible, explains pathophysiology, correlates with Eichenholtz, and predicts amputation. The unique intraneural vasculopathy observed contributes to CNA etiology.

Novel FEMASK-score, a histopathologic assessment for destructive Charcot neuropathic arthropathy, reveals intraneural vasculopathy and correlates with progression and best treatment

BackgroundCharcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy. DesignRetrieval of surgical pathology midfoot specimens from Charcot patients (2012–2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (<half 40× hpf) periarticular bone fragments to resolution, we devised and applied a Charcot neuropathic arthropathy novel FEMASK-score (named after coauthors: Fanburg-Smith, Frauenhoffer, Flemming, Fritsche, Elfar, Murie, Aynardi, Stauch, Smith, King, and Klein): 0 (initial) = the observed intraneural arteriolosclerosis in all diabetic neuropathic patient specimens (not observed in other diabetic nerves); and finally scored with the most destruction observed: 1 = large bone fragments without host histiocytic response; 2 = mixed bone fragments with host histiocytic response; 3 = small minute bone spicules resorption to fibrosis. Eichenholtz stage and outcome were then compared. ResultsForty-eight cases of Charcot neuropathic arthropathy included 34 males and 14 females, mean age 60.3 and age range 28–83 years, with clinical diabetes mellitus (predominantly Type II) and longstanding neuropathy. Elevated HbA1C, Eichenholtz stage, American Society of Anesthesia score, and Charlson comorbidity index indicated initial clinical amputation. Pathologic specimens varied from fixation tissue to amputation. In addition to neurotraumatic, neurovascular and inflammatory findings, a distinctive intraneural hyalinized arteriolosclerosis was observed. FEMASK-scores: 1 = 10%, 2 = 58%, and 3 = 32%. Score comparisons were 98% accurate compared with Eichenholtz and 98% reproducible among pathologists. FEMASK 2 and 3 correlate with clinical need for amputation. ConclusionsOur novel Charcot neuropathic arthropathy FEMASK-score classification, derived from the largest cohort of diabetic neuropathic specimens, is reproducible, explains pathophysiologic progression of destructive phase of Charcot, correlates with Eichenholtz, and predicts progression to or clinical need for amputation. The unique intraneural vasculopathy observed contributes to Charcot neuropathic arthropathy etiology.

Novel Pathologic-Scoring for Charcot Arthropathy with Intraneural Observations

Category:Diabetes, Hindfoot, Midfoot/ForefootIntroduction/Purpose:Charcot arthropathy is a destructive joint disorder in patients with longstanding neuropathy, commonly related to Type II diabetes (T2DM). The diagnosis is historically classified via the radiologic Eichenholtz staging system (E-score). The purpose of this study is to examine histopathologic features and develop a correlative pathologic score for Charcot neuroarthropathy.Methods:Patients undergoing lower limb surgery with a clinical diagnosis of midfoot-ankle Charcot neuroarthropathy were included for study. Clinical data, radiology, E-score (1-3), and surgical pathology specimens were reviewed to evaluate skin, adipose, vessel, skeletal muscle, nerve, bone, and bone fragments embedded in synovium. Charcot pathology-score 1 (P-score, CPSI) = large bone fragments (> half 40x hpf objective) without host histiocytic response. CPSII = mixed large and small bone fragments with/without host histiocytic response, CPSIII = small to minute spicules to almost complete resorption/absence of bone fragments with histiocytic/fibrosis-reactive response, were scored by the authors in a blinded fashion.Results:Forty-two patients (32 males and 10 females) were included in analyses with a mean age of 59.9 years (median age: 60, range 28-83). Clinical risk factors for Charcot included T2DM and longstanding neuropathy. Elevated HbA1C, E-Score, preoperative American Society of Anesthesia score, and Charlson comorbidity index were predictors of amputation. Majority of pathologic specimens examined had superficial ischemic ulceration, dermal fibrosis, cellulitis, medial hypertrophy, atherosclerosis, skeletal muscle atrophy, and nerve hypertrophy with intraneural edema and perineural fibrosis. Osteomyelitis was present in >70%. P-scores CPSI = 6%, CPSII = 44%, CPSIII = 50% correlate with E-scores in 98% of cases without interobserver variability. Minor difference from E-score to P-score (2%) was due to sampling. Novel neuropathy change includes observation of intraneural vasculopathy (arteriolosclerosis) in evaluable nerves.Conclusion:CPS is reliable and reproducible and can be performed with adequate synovial sampling. Charcot progresses from large bone fragments in synovium to mixed size with histiocytic response, and final small/resorbed fragments with marked host response/fibrosis. Intraneural vasculopathy likely plays a role in Charcot. Charcot pathology-score (P-score) strongly correlates with clinicoradiologic Eichenholtz-score (E-score).

Vitamin A deficiency mimicking CNS demyelination

Introduction: Severe vitamin A deficiency causing significant visual impairment is rarely encountered in children. We present a case of optic neuropathy associated with Vitamin A deficiency mimicking central nervous system (CNS) demyelination. Case: A three year old girl with a background of cow’s milk protein intolerance presents with a gradual history of painless visual loss over three weeks. This only became noticeable to her family when she was unable to see close objects. An urgent ophthalmology opinion was sought, which demonstrated evidence of bilateral optic neuropathy. MR imaging of her brain and spine demonstrated multiple areas of subtle high signal changes including the cervical cord and splenium of the corpus callosum. Although imaging was suggestive of demyelination, her ophthalmology findings were more indicative of a long-standing neuropathy. Steroid therapy was therefore held off pending further investigations, which confirmed an undetectable Vitamin A level. This was treated with Vitamin A supplementation, which has resulted in stability of her vision and visual fields. Discussion: Nutritional optic neuropathies are uncommon but need to be thought of in high risk patients. On further review of our patient’s history, she was found to be a very picky eater with limited intake of products rich in Vitamin A. CNS demyelination is not a reported feature of Vitamin A deficiency and the subtle imaging changes seen in our case are likely to be coincidental. Early diagnosis and treatment of Vitamin A deficiency is crucial in preserving vision and preventing further visual deterioration. Conclusion: In children who present with gradual visual loss and optic neuropathy, consideration should be given to nutritional deficiencies such as Vitamin A deficiency. The presence of subtle changes on imaging suggestive of demyelination may sometimes be a red herring and clinical correlation is needed to clinch the correct diagnosis.

Case 2: Long-standing neuropathy with acute onset of weakness

A 16-year-old girl with presumed Charcot-Marie-Tooth disease presented to the emergency department with an acute onset of lower limb weakness. She was unable to walk where previously she had been fully ambulatory. One month before presentation, she had a three-week history of abdominal pain. Five days before presentation, she developed bilateral shoulder and upper back pain. The morning of her presentation, she had difficulty getting up off the floor and getting in and out of the bathtub. She reported that her legs were numb and ‘wobbly’. She had no presyncopal symptoms. She denied urinary incontinence. Bowel dysfunction was difficult to assess because she usually stooled once per week. She had no fevers or night sweats. Her history was significant for orthopaedic surgeries. She was followed for bilateral pes cavus deformities and progressive right foot varus deformity for which she had required surgery several years earlier. Her presumed diagnosis of Charcot-Marie-Tooth disease was based on her orthopaedic findings and her family history. Her mother, maternal aunt and other relatives on her mother’s side had been diagnosed by genetic testing. The patient herself had not had genetic testing and was not followed by a neurologist at the time of presentation. As a result, her premorbid neurological examination was unknown. A physical examination at presentation revealed stable vital signs with a blood pressure of 110/66 mmHg. Her lower limbs were weak, with the right side weaker than the left. The proximal muscles were more severely affected than the distal muscles. She had decreased sensation to pinprick, light touch, and a temperature to the level of T8 to T10 on the left and T4 on the right. Proprioception was inconsistent in the toes, and vibration sense was also decreased in the toes, but was normal at the ankles. Her lower limb reflexes were absent (it was not clear whether she had reflexes present in the past). Plantar responses were flexor and anal tone was normal. The laboratory investigations (complete blood count, electrolytes, calcium, magnesium, phosphate, liver enzymes, lactate dehydrogenase, creatine kinase and erythrocyte sedimentation rate) were unremarkable. A magnetic resonance imaging screen of her spine was normal. She was admitted to hospital for observation and further workup. The day after her admission, the patient’s lower limbs continued to weaken. She became incontinent. After four days, a magnetic resonance imaging screen was performed which revealed the diagnosis.

Vasomotor reflexes in the fingertip skin of patients with type 1 diabetes mellitus and leprosy

Fingertip skin blood flow was measured by laser Doppler flowmetry (as LDflux) under environmental conditions promoting vasodilation in Scottish patients with diabetes mellitus and Indian patients with leprosy. The reflex control of fingertip blood flow was assessed by measuring the reduction in LDflux induced by deep inspiratory gasp (IG) and cold challenge (CC) of immersing the contralateral hand in cold water. The uncomplicated diabetic patients showed normal vasomotor reflexes and an increased, though non significant, LDflux level (p < 0.06). The patients with diabetic neuropathy had resting LDflux levels significantly less than the uncomplicated group and also had substantial impairment of both IG and CC reflexes. Those with retinopathy (but no clinically apparent neuropathy) had LDflux within the normal range, but they showed minor evidence of impairment of the vasomotor reflexes. The uncomplicated newly registered leprosy patients had reduced LDflux and substantial impairment of CC reflexes. These changes were more marked in newly registered leprosy patients with clinical evidence of neuropathy. Leprosy patients with long-standing neuropathy requiring orthopaedic treatment had LDfluxes so greatly reduced that measurement of vasomotor reflexes was not practicable. The CC reflex was more severely affected than the IG reflex and more frequently absent in leprosy patients, possibly because of associated sensory neuropathy affecting the afferent limb of this response. Thus laser Doppler flowmetry can detect impairment of reflex control of fingertip blood flow in both diabetes mellitus and leprosy, but there are functional differences in the pattern of autonomic impairment between the diseases, suggesting differences in the pathogenesis of nerve damage.

Charcot's disease in diabetic patients

Although Charcot's disease and its association with diabetes have been described many times in the literature, it is still often misdiagnosed and incorrectly treated as osteomyelitis, arthritis, or gout. The best safeguard is a high index of suspicion. A warm, swollen foot in a diabetic patient with long-standing neuropathy without local or systemic signs of infection must be considered Charcot's disease until proven otherwise. The principal treatment is total abstinence from putting weight on the foot until warmth, swelling, and redness subside. Protective weight-bearing methods may then be slowly instituted.

Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry.

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.