Peripheral Sensorimotor Polyneuropathy Research Articles

Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy.

Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called "amyloid". The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.

Effects of vitamin D3 (cholecalciferol) supplementation on diabetic polyneuropathy in patients diagnosed with diabetes mellitus

Abstract Introduction: Peripheral sensorimotor polyneuropathy is present in nearly half of the patients diagnosed with diabetes mellitus. Over the past 10 years, animal and human studies have suggested that vitamin D3 treatment may have a role in preventing or reducing neuropathic complaints and symptoms. Material and method: Our clinical, prospective, interventional, placebo-controlled study investigated the therapeutic effect of 2.000 IU oral cholecalciferol administered for three months on diabetic polyneuropathy. Patients treated with vitamin D and B, thioctic acid, and other analgesics were excluded. Using the single-blind technique, they were randomly assigned into vitamin D-treated and placebo-treated groups. In addition to recording anamnestic data, the study included - a Toronto Clinical Neuropathy Scoring System and Michigan Neuropathy Screening Instrument based - questionnaire to assess subjective symptoms and a physical examination including sensory tests (fine touch-, temperature awareness, pain-, vibration perception). Vitamin D levels were measured. After three months of therapy, the examination was repeated. Results: Most of the patients were found to have vitamin D deficiency (36% of the total population) or insufficiency (43%). In the cholecalciferol-treated group, but not in the control group, subjective symptoms decreased in intensity and/or frequency, and a significant improvement in the overall complaint scale was observed (p = 0.006), but no change regarding the sensory tests (p > 0.05). Conclusions: Our results show that oral administration of cholecalciferol for three months significantly reduced subjective symptoms and neuropathic pain as assessed by our questionnaire, however, there was no significant change in the results of the sensory tests. Vitamin D deficiency/insufficiency was common in diabetic patients (79% in our population), therefore screening is recommended.

Paraneoplastic Optic Neuropathy as an Initial Clinical Manifestation of Small Cell Lung Cancer. A Case Report

Paraneoplastic optic neuropathy (PON) is a very rare condition. In this study, a case of PON is presented, with the first complaint by the patient being painless vision loss in one eye. In the follow-up of our case, optic neuropathy developed in the fellow eye. Electromyography examination performed due to diffuse body pain and motor loss in the left extremity was compatible with peripheral sensorimotor polyneuropathy. Lung biopsy was planned due to the EMG result and lymphadenopathy detection in thorax computed tomography (CT). The biopsy result of the patient was reported as nonspecific hyperplasia. As the patient’s complaints increased, a paraneoplastic antibody panel was requested and CV2 / CRMP5 antibody was found to be positive. Thereupon, as a result of the repeated biopsy, our patient was diagnosed with small cell lung cancer. We think that paraneoplastic optic neuropathy should be considered in the differential diagnosis in patients of advanced age, smokers, painless subacute vision loss, optic disc swelling, and research in this direction should be insisted on, as in our case.

Development and Comparative Efficacy of Lagos Neuropathy Protocol for Improving Recovery of Symptom and Functional Independence Performance in Individuals with Diabetic Peripheral Sensorimotor Polyneuropathy.

Diabetic peripheral sensorimotor polyneuropathy (DPSP) has been treated with sketchy outcomes and available approaches are not applicable for self-administration. This study developed protocol for managing symptoms of DPSP and assessed its comparative efficacy. Study developed Lagos Neuropathy Protocol (LNP) through existing concept in DPSP and tested its safety, clinical applicability, and ease of self-administration. Its efficacy was compared with Buerger-Allen Exercise (BAE) by involving 31(11males) with DPSP, randomized into LNP and BAE and treated for 10-week. Toronto Clinical Scoring System was used to diagnose DPSP while Diabetic Neuropathy Examination was used to diagnose distal polyneuropathy. Sensory/pressure perception was assessed using 10 g-monofilament while Short Physical Performance Battery, Bergs Balance Scale and Visual Analogue Scale was used to assess functional performance, strength and balance, and pain respectively. LNP has three domains: sensory/pressure/proprioception, strength/balance, and pain/swelling. Most (80%) of the participants rated the LNP as excellently safe while the rest (20%) rated as very good in safety. All the participants rated LNP excellent in terms of self-administration and suitability for clinical use without adverse effect. The mean age of the participants for the comparative phase was 66.20±9.48years while their length of diagnoses of diabetes was 15.80±13.35years. About a third (32.5%) had DPSP. Both LNP and BAE had significant improvement (p<0.05) in sensory/pressure perception, pain, strength and balance, and functional performance but LNP had better significant improvement. LNP is safe, good for self-administration, clinically applicable and efficacious in improving sensory/pressure perception, balance, pain and functional performances in individuals with DPSP.

The silent occurrence of cerebral small vessel disease in nonelderly patients with type 2 diabetes mellitus.

The prevalence of cerebral small vessel disease (SVD) increases in elderly patients with type 2 diabetes (T2DM), exacerbating cognitive decline. However, the prevalence and the severity of SVD in dementia-free nonelderly T2DM patients were largely unknown. Our primary aim is to investigate SVD in such patients, with a specific focus on the correlation between SVD and diabetic peripheral sensorimotor polyneuropathy (DSP). We recruited 180 young and middle-aged subjects without cognitive impairment (106 with T2DM, 74 controls). Signs of cerebral SVD on magnetic resonance image were investigated, and the overall SVD burden was evaluated by a combined score. Patients with T2DM underwent further detailed DSP assessment. Regression models were used to investigate the association of SVD with the presence of T2DM, and the associations of the prevalence and severity of SVD and DSP were also explored in patients with T2DM. The prevalence of microbleeds and overall burden of SVD were significantly higher in T2DM patients than in the controls. Further, the presence of DSP related to an increased risk of SVD after adjustment in diabetic group. Moreover, Toronto Clinical Scoring System values were positively associated with the increased SVD scores, and bilateral sural sensory nerve conduction velocities were negatively associated with increasingly severity of SVD scores. The current findings extended the increasing prevalence of SVD to dementia-free nonelderly patients with T2DM, suggesting that the time for cognitive screening and prevention might be moved forward in T2DM patients, especially for those with DSP.

Donor risk factors in pancreas transplantation.

The aim of the work was to analyze and expose the donor and recipient risk factors in pancreas transplantation. In the following paper, we exposed the 2018 Spanish Consensus Document on Donor and Recipient Selection Criteria for Pancreas Transplantation. An assessment of the previous Selection Criteria for Donors and Recipients of Pancreas Transplantation, published in 2005 by the Spanish Pancreas Transplant Group (GETP) and the National Transplant Organization (ONT) was performed. A literature review was performed using Cochrane Library, PubMed and Google Scholar databases. Some of the following terms were used for the literature search: “Diabetes Mellitus,” “Pancreas Transplantation,” “Insulin-Secreting Cells,” “Pancreas Allograft Thrombosis,” “Allograft Pancreatitis,” “Donors’ Risk Factors,” “Recipients’ Risk Factors,” “Pancreas Allograft Rejection” and “Pancreas Allograft Survival.” After an extended search, different inclusion criteria were established. Articles and documents with abstracts of full text and in English or Spanish language were selected. Subsequently, different scientific meetings took place during 2015 and 2016 by the GETP. Finally, the updated criteria were published by the GETP and ONT in 2018. Several risk factors have been described in pancreas transplantation that can be divided into donor risk factors: Advanced age (> 50 years); high body mass index (BMI) (> 30 kg/m2); cause of death (e.g., stroke); previous hyperglycemia; hyperamylasemia; cold ischemia time (greater than 8 or 12 h, depending on the type of donation); the use of vasopressors in the intensive care unit or cardiac arrest; and the macroscopic aspect of the pancreas allograft. The following are recipient risk factors: Advanced age (> 50 years); active smoking; high BMI (> 30 kg/m2); and peripheral artery disease or sensorimotor polyneuropathy. Based on the aforementioned parameters, different selection criteria have been established for the recipients depending on the type of pancreas transplantation. Knowledge of the risk factors for pancreas transplantation allows the establishment of reliable selection criteria for choosing donors and recipients.

Surgical peripheral nerve decompression for the treatment of painful diabetic neuropathy of the foot – A level 1 pragmatic randomized controlled trial

AimsTo assess the efficacy of surgical decompression of lower extremity nerves for the treatment of painful diabetic peripheral sensorimotor polyneuropathy (DPN). MethodsPeople with painful diabetic neuropathy were randomized single-blind to a lower extremity decompression surgery (n = 12) or observation (n = 10) for 1 year. ResultsPain was the primary outcome assessed with 2 measures. The McGill pain visual analogue scores over time changed within the groups (p for time < 0.0001), and changed differently over time within the groups (p for group × time = 0.0138). The NeuroQoL pain sensitivity analysis significantly changed from baseline to 12 months comparing intervention to control (p = 0.0079), and the joint effect of group and time on pain scores was statistically significant (p for group × time = 0.0009). At the study end-point of 12 months, intervention group participants had over 3 times the odds of rating their pain as “better” compared to “unchanged” or “worse” in the control group (p = 0.0177). ConclusionsSurgical decompression of lower limb nerves was an effective treatment for decreasing pain in patients with DPN and superimposed nerve compressions.

Mixed cryoglobulinemia: a diagnostic and therapeutic challenge

Mixed cryoglobulinemia is frequently secondary to hepatitis C virus infection. Diagnosis and therapeutic management are challenging, depending on the spectrum and severity of manifestations, as well as on the presence...

In vivo corneal confocal microscopy in diabetes: Where we are and where we can get.

In vivo corneal confocal microscopy (IVCCM) is a novel, reproducible, easy and noninvasive technique that allows the study of the different layers of the cornea at a cellular level. As cornea is the most innervated organ of human body, several studies investigated the use of corneal confocal microscopy to detect diabetic neuropathies, which are invalidating and deadly complications of diabetes mellitus. Corneal nerve innervation has been shown impaired in subjects with diabetes and a close association between damages of peripheral nerves due to the diabetes and alterations in corneal sub-basal nerve plexus detected by IVCCM has been widely demonstrated. Interestingly, these alterations seem to precede the clinical onset of diabetic neuropathies, paving the path for prevention studies. However, some concerns still prevent the full implementation of this technique in clinical practice. In this review we summarize the most recent and relevant evidences about the use of IVCCM for the diagnosis of peripheral sensorimotor polyneuropathy and of autonomic neuropathy in diabetes. New perspectives and current limitations are also discussed.

Severe Axonal Peripheral Polyneuropathy Revealing a Systemic Lupus Erythematosus: About One Case

Aim: We report a case of acute and severe sensorimotor peripheral polyneuropathy (with a severe motor damage) revealing a lupus. Case Presentation: A 48-year-old female patient was interned in rheumatology for a chronic polyarthritis. Four days after her hospitalisation, she was presenting a flask distal and proximal tetraparesia, with rapidly progressive installation. Electromyogram showed severe acute axonal sensorimotor polyneuropathy. The antinuclear antibody was positive as the anti-ds-DNA antibodies. The evolution has been unsatisfactory despite the high-dose corticotherapy and the immunosuppressor. Conclusion: Even if it is rare, peripheral neuropathy can be a lupus discovery circumstance.

Neurologic involvement in scleroderma: A systematic review

To perform a systematic review of neurologic involvement in Systemic sclerosis (SSc) and Localized Scleroderma (LS), describing clinical features, neuroimaging, and treatment. We performed a literature search in PubMed using the following MeSH terms, scleroderma, systemic sclerosis, localized scleroderma, localized scleroderma "en coup de sabre", Parry-Romberg syndrome, cognitive impairment, memory, seizures, epilepsy, headache, depression, anxiety, mood disorders, Center for Epidemiologic Studies Depression (CES-D), SF-36, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9), neuropsychiatric, psychosis, neurologic involvement, neuropathy, peripheral nerves, cranial nerves, carpal tunnel syndrome, ulnar entrapment, tarsal tunnel syndrome, mononeuropathy, polyneuropathy, radiculopathy, myelopathy, autonomic nervous system, nervous system, electroencephalography (EEG), electromyography (EMG), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA). Patients with other connective tissue disease knowingly responsible for nervous system involvement were excluded from the analyses. A total of 182 case reports/studies addressing SSc and 50 referring to LS were identified. SSc patients totalized 9506, while data on 224 LS patients were available. In LS, seizures (41.58%) and headache (18.81%) predominated. Nonetheless, descriptions of varied cranial nerve involvement and hemiparesis were made. Central nervous system involvement in SSc was characterized by headache (23.73%), seizures (13.56%) and cognitive impairment (8.47%). Depression and anxiety were frequently observed (73.15% and 23.95%, respectively). Myopathy (51.8%), trigeminal neuropathy (16.52%), peripheral sensorimotor polyneuropathy (14.25%), and carpal tunnel syndrome (6.56%) were the most frequent peripheral nervous system involvement in SSc. Autonomic neuropathy involving cardiovascular and gastrointestinal systems was regularly described. Treatment of nervous system involvement, on the other hand, varied in a case-to-case basis. However, corticosteroids and cyclophosphamide were usually prescribed in severe cases. Previously considered a rare event, nervous system involvement in scleroderma has been increasingly recognized. Seizures and headache are the most reported features in LS en coup de sabre, while peripheral and autonomic nervous systems involvement predominate in SSc. Moreover, recently, reports have frequently documented white matter lesions in asymptomatic SSc patients, suggesting smaller branches and perforating arteries involvement.

Adverse event profile by therapy cycle for vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in platinum-resistant ovarian cancer.

5572 Background: Vintafolide (EC145), a folic acid/desacetylvinblastine conjugate, binds with high affinity to folate receptors expressed in epithelial ovarian cancers. This analysis evaluated the incidence of adverse events (AEs) by treatment cycle and as a percent of total treatment cycles administered in the PRECEDENT trial, a randomized open-label study of subjects with platinum-resistant ovarian cancer receiving either vintafolide+PLD or PLD alone. Methods: Women ≥18 years old with ECOG status 0-2 and exposure to ≤2 prior systemic cytotoxic regimens were randomized 2:1 to vintafolide (2.5 mg IV tiw, weeks 1 and 3, q28 days)+PLD (50 mg/m2 IV day 1, q28 days) or PLD alone (same dose + schedule). AEs in the safety population (received at least 1 dose of study drug) were evaluated by cycle. Results: 157 patients received a total of 720 treatment cycles (518 vintafolide+PLD, 202 PLD alone). AEs (all grades, vintafolide+PLD vs PLD alone): 85.9% and 80.2% of cycles. Anemia, neutropenia, and thrombocytopenia were observed in 16.6% (vs 10.4% administered PLD alone), 19.1% (vs 10.4%), and 2.7% (vs 3.0%) of all cycles, respectively. Febrile neutropenia was observed in 0.2% (vs 0.5%) of cycles, respectively. Stomatitis and hand-foot syndrome (HFS) occurred in 16.6% (vs 22.8%) and 19.1% (vs 15.8%) of cycles, respectively. Peripheral sensory, motor, or sensorimotor neuropathy or polyneuropathy occurred in 10.1% (vs 2.5%) of cycles, and constipation and small intestinal obstruction/ileus were observed in 12.7% (vs 10.4%) and 2.9% (vs 4.0%) of cycles, respectively. Fatigue was similar between arms—15.8% of vintafolide+PLD vs 14.9% of PLD cycles. All AEs were noncumulative except for HFS, which for both arms increased in frequency through Cycle 6 compared with Cycles 1 and 2. Grade 3/4 AEs (vintafolide+PLD vs PLD alone): 29.3% vs 18.3% of cycles. Conclusions: After the number of treatment cycles was accounted for, anemia, neutropenia, and neuropathy were numerically greater in patients on vintafolide+PLD. Thrombocytopenia, constipation, small intestinal obstruction/ileus, fatigue, and HFS were similar. Stomatitis was numerically greater in patients administered PLD alone. Clinical trial information: NCT00722592.

Severe ataxia with neuropathy in hereditary gelsolin amyloidosis

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder caused by a G654A or G654T gelsolin mutation, reported from Europe, North America, and Japan. Principal clinical signs are corneal lattice dystrophy, cutis laxa and cranial neuropathy, often deleterious at advanced age. Peripheral neuropathy, if present, is usually mild. We report a 78- year old male Finnish patient who presented with ataxia and mainly sensory peripheral polyneuropathy (PNP) signs, causing severe disability and ambulation loss. Electrophysiological studies showed severe generalized chronic mainly axonal sensorimotor PNP with facial paralysis. In magnetic resonance imaging proximal lower limb and axial muscle atrophy with fatty degeneration as well as moderate spinal cord atrophy were seen. A G654A gelsolin mutation was demonstrated but no other possible causes of his disability were found. At age 79 he became bedridden and died of pulmonary embolism. Neuropathological examination revealed marked gelsolin amyloid deposition at vascular and connective tissue sites along the entire length of the peripheral nerves extending to the spinal nerve roots, associated with severe degeneration of nerve fibers and posterior columns. Our report shows that advanced AGel amyloidosis due to degeneration of central and distal sensory nerve projections results in deleterious ataxia with fatal outcome. Severe posterior column atrophy may reflect radicular AGel deposition, although even altered gelsolin - actin interactions in neural cells possibly contribute to neurodegeneration with successive ataxia in carriers of a G654A gelsolin mutation.

Poster 197: Inflammatory Myopathy in a Diabetic Presenting With Foot Drop: A Case Report

Setting: Outpatient clinic. Patient: A 29-year-old man referred for electrodiagnostics with 1 year complaint of progressive foot drop and ataxia. Case Description: Patient has medical history of poorly controlled diabetes type 1 (diagnosed 14 years prior), hyperlipidemia (with current statin use), hypertension, and depression. History of present illness revealed proximal and distal weakness in upper and lower extremities and numbness in stocking and glove distribution. Lumbar magnetic resonance imaging showed disk herniations with no stenosis. The patient denied back pain, radicular pain, muscle aches, or family history of neurologic conditions. Physical exam revealed diffuse atrophy, proximal and distal weakness with trace bilateral ankle dorsiflexion, absent reflexes, and normal muscle tone. Electrodiagnostics revealed a sensorimotor peripheral polyneuropathy with neuropathic findings on electromyography (EMG) without specific myopathic features. Lab studies revealed CPK greater than 1000, elevated aldolase, ESR greater than 100, and a negative rheumatologic panel. Muscle biopsy was suggestive of a chronic myopathy, possibly inflammatory, with features of neurogenic atrophy. Assessment/Results: This patient's clinical picture and diagnostics are suggestive of multifactorial weakness—due to a chronic inflammatory myopathy—polymyositis versus statin-induced myopathy, with a superimposed diabetic neuropathy. The patient has been discontinued from statins, started on corticosteroids and azathioprine, fitted with bilateral ankle foot orthoses, and treated with physical therapy. His functional status remains stable with ongoing treatment. Conclusions: Correlation of thorough history, physical exam, and diagnostics is essential for appropriate diagnosis and treatment. EMG findings for this patient were suggestive of a neuropathic process, while physical exam also suggested a myopathic process. Through laboratory and histologic studies a more complete pathophysiology and treatment plan was formed. It is important to remember that weakness can be multifactorial. Complex cases where history and physical do not correlate with findings necessitate further diagnostic investigation, consideration, and cross-specialty physician collaboration to achieve the best patient outcomes.

Usefulness of a new indicator test for the diagnosis of peripheral and autonomic neuropathy in patients with diabetes mellitus

The aim of the present study was to assess the performance of a new indicator test (NIT), based on the measurement of sweat production after exposure to dermal foot perspiration, in the diagnosis of both peripheral sensorimotor polyneuropathy (PSN) and autonomic neuropathy in patients with diabetes. One hundred and seventeen diabetic patients were examined. PSN was assessed using the neuropathy symptoms score, the neuropathy disability score and the vibration perception threshold. Cardiac autonomic neuropathy (CAN) was assessed using the battery of the four classical standardized tests proposed by Ewing et al., Diabetes Care 1985; 8: 491-498. Sudomotor dysfunction was assessed using the NIT. Fifty patients (42.7%) had PSN and 44 patients (37.6%) had CAN. Of the 50 patients with PSN, 43 had a positive NIT (sensitivity 86%) and, out of the 67 patients without PSN, a negative NIT was obtained in 45 patients (specificity 67%). The positive and the negative predictive value of the NIT in detecting PSN were 66.2 and 86.5%, respectively. The sensitivity and specificity of NIT in detecting CAN was 59.1 and 46.5%, respectively. In the case of severe CAN, the sensitivity was increased to 80.9% and the specificity to 50%. The NIT has good sensitivity and negative predictive value for diagnosis of PSN and can be used as a screening method for detection of this complication in patients with diabetes. In addition, the test has a low sensitivity for detection of autonomic neuropathy in patients with milder forms of CAN.

Severe ataxia with neuropathy in hereditary gelsolin amyloidosis: A case report

Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder caused by a G654A or G654T gelsolin mutation, reported from Europe, North America, and Japan. Principal clinical signs are corneal lattice dystrophy, cutis laxa and cranial neuropathy, often deleterious at advanced age. Peripheral neuropathy, if present, is usually mild. We report a 78-year-old male Finnish patient who presented with ataxia and mainly sensory peripheral polyneuropathy (PNP) signs, causing severe disability and ambulation loss. Electrophysiological studies showed severe generalized chronic mainly axonal sensorimotor PNP with facial paralysis. In magnetic resonance imaging proximal lower limb and axial muscle atrophy with fatty degeneration as well as moderate spinal cord atrophy were seen. A G654A gelsolin mutation was demonstrated but no other possible causes of his disability were found. At age 79 years he became bedridden and died of pulmonary embolism. Neuropathological examination revealed marked gelsolin amyloid deposition at vascular and connective tissue sites along the entire length of the peripheral nerves extending to the spinal nerve roots, associated with severe degeneration of nerve fibers and posterior columns. Our report shows that advanced AGel amyloidosis due to degeneration of central and distal sensory nerve projections results in deleterious ataxia with fatal outcome. Severe posterior column atrophy may reflect radicular AGel deposition, although even altered gelsolin–actin interactions in neural cells possibly contribute to neurodegeneration with successive ataxia in carriers of a G654A gelsolin mutation.

Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency

General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.

Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy.

The aim of the current study was to determine the validity of the Toronto Clinical Scoring System (CSS) in reflecting the presence and severity of diabetic peripheral sensorimotor polyneuropathy (DSP) as determined by myelinated fiber density (FD) on sural nerve biopsy. Eighty-nine patients with both type 1 and type 2 diabetes, ascertained from a large therapeutic randomized controlled trial, were included in this cross-sectional, observational cohort study. Morphological severity of DSP was expressed as the FD in the sural nerve biopsy. The Toronto CSS was applied to all patients to determine a clinical neuropathy score. General linear regression models were used to assess the relationship between the morphological severity of DSP and the Toronto CSS. The Toronto CSS showed a significant negative correlation with sural nerve FD (R(2) = 0.256, P < 0.0001). The Toronto CSS was lower in those with better glycemic control (HbA(1c) </=8%). Sural nerve FD and the Toronto CSS showed strong correlations with electrophysiology, by both summed amplitude and summed conduction velocity values. The Toronto CSS is a valid instrument to reflect the presence and severity of DSP as measured by sural nerve morphology and electrophysiology. The results of the current study underscore the interrelationships between clinical deficits, electrophysiological findings, and morphological changes in DSP. This evidence suggests that the Toronto CSS may prove useful in documenting and monitoring DSP in the clinic and in clinical research trials.

Congenital hypomyelination neuropathy in a newborn infant: unusual cause of diaphragmatic and vocal cord paralyses

We report a case of congenital hypomyelination neuropathy presenting at birth. The infant had generalized hypotonia and weakness. There was decreased respiratory effort along with a right phrenic nerve and left vocal cord paralyses. Tongue fasciculations were present. Deep tendon reflexes were absent in the upper extremities and hypoactive (1+) in the lower extremities. Magnetic resonance imaging of the head revealed no intracranial abnormalities, including normal cerebral myelination. Nerve conduction study showed absence of motor and sensory action potentials in the hands when the nerves in the upper limbs were stimulated. A motor response could be elicited only in the proximal leg muscles. Needle electromyography study was normal in the proximal limb muscles, but showed active denervation in the distal muscles of the arm and leg. These findings were thought to be consistent with a length‐dependent sensorimotor peripheral polyneuropathy of axonal type with greater denervation of the distal muscles. A biopsy of the quadriceps muscle showed mild variability in fiber diameter, but no group typing or group atrophy. The muscle fibers showed no intrinsic abnormalities. Biopsy of the sural nerve showed scattered axons with very thin myelin sheaths. There was also a nearly complete loss of large diameter myelinated fibers. No onion bulb formations were noted. These findings were thought to be consistent with congenital hypomyelination neuropathy with a component of axonopathy. DNA analysis for identification of previously characterized mutations in the genes MPZ, PMP22, and EGR2 was negative. Several attempts at extubation failed and the infant became increasingly ventilator‐dependent with increasing episodes of desaturation and hypercapnea. He also developed increasing weakness and decreased movement of all extremities. He underwent surgery at 2 months of age for placement of a gastrostomy tube and a tracheostomy. He was discharged from the hospital on a ventilator at 6 months of age. The infant was 13 months old at the time of submission of this report. Although he appears cognitively normal, he remains profoundly hypotonic and is on a home ventilator. There was no evidence of progressive weakness. Congenital hypomyelination neuropathy is a rare form of neonatal neuropathy that should be considered in the differential diagnosis of a newborn with profound hypotonia and weakness. It appears to be a heterogeneous disorder with some of the cases being caused by specific genetic mutations.

Cranial and peripheral neuropathy due to Epstein-Barr virus infection.

A case of Epstein-Barr virus infection with neurological complications is described. An 18-year-old man developed cranial neuropathy and peripheral sensorimotor polyneuropathy three weeks after a sore throat. Though severely affected...