Peripheral Nervous System Involvement Research Articles

Multidisciplinary approach to Fabry disease: from the eye of a neurologist.

Fabry Disease (FD) is an X-linked lysosomal storage disease that emerges as a result of the mutations in the galactosidase A gene encoding alpha-galactosidase. The peripheral nervous system (PNS) involvement manifests itself as acroparesthetic complaints due to the small-fiber involvement. Our goal was to assess the PNS involvement of 14 patients with FD both clinically and electrophysiologically besides the other systemic features. 14 patients (11 female and 3 male) of the same family whose enzyme level and genetic mutation analysis confirmed the FD diagnosis were evaluated retrospectively in terms of systemic and neurological findings of the FD. Neurological examination and nerve conduction studies were performed to evaluate the PNS involvement. PNS involvement was more common in females. Eight of the patients had acroparesthesia. The neurological examinations of all patients were normal. Two patients presented sensory axonal polyneuropathy, one of whom had no acroparesthesia. Other patients with acroparesthesia had normal nerve conduction studies. There was no significant relationship between the presence of acroparesthesia and the results of conduction studies (p > 0.05). Acroparesthetic complaints in patients with normal results were attributed to small-fiber involvement. Since small-diameter nerve fibers cannot be evaluated by routine conduction studies, especially in the early stages of FD, these studies may be normal. Early diagnosis through the symptoms such as acroparesthesia may contribute to the survival of the patient by preventing and/or delaying the development of renal, cardiac, and cerebrovascular diseases, which are the main causes of morbidity and mortality.

Chorea-ballism as a dominant clinical manifestation in heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation in mitochondrial genome: a case report

BackgroundMitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, the most common maternally inherited mitochondrial disease, can present with a wide range of neurological manifestations including both central and peripheral nervous system involvement. The most frequent genetic mutation reported in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome is A3243G in MT-TL1 gene. Stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature constitute the known presentations in this syndrome. Among the abnormal involuntary movements in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome, myoclonus is the commonest. Other movement disorders, including chorea, are rarely reported in this disorder.Case presentationA 14-year-old South Asian boy from rural Bengal (India), born of a second degree consanguineous marriage, with normal birth and development history, presented with abnormal brief jerky movements involving his trunk and limbs, with recurrent falls for 10 months. We present here a case of heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation, in which the clinical picture was dominated by a host of involuntary abnormal movements including chorea-ballism, myoclonus, and oromandibular dystonia in a backdrop of cognitive decline, seizure, and stroke-like episode. A final diagnosis was established by muscle biopsy and genetic study. Haloperidol was administered to control the involuntary movements along with introduction of co-enzyme Q, besides symptomatic management for his focal seizures. Six months into follow-up his seizures and abnormal movements were controlled significantly with slight improvement of cognitive abilities.ConclusionThe dominance of hyperkinetic movements in the clinical scenario and the finding of a point mutation A3251G in MT-TL1 gene make this a rare presentation.

Alterations in Blood-Brain Barrier Permeability in Patients with Systemic Lupus Erythematosus.

Neuropsychiatric systemic lupus erythematosus refers to central and peripheral nervous system involvement, which may occur secondary to antineuronal antibodies crossing the blood-brain barrier that preferentially target cells in the hippocampus leading to abnormal hypermetabolism and atrophy. Thus, we hypothesized that alterations in BBB permeability, detected on dynamic contrast-enhanced MR imaging, occur in the hippocampus in patients with systemic lupus erythematosus before development of neuropsychiatric systemic lupus erythematosus. Six patients with systemic lupus erythematosus without neuropsychiatric systemic lupus erythematosus and 5 healthy controls underwent dynamic contrast-enhanced MR imaging with postprocessing into BBB permeability parameters (K trans and Ve) and CBF. Standardized methods selected ROI sampling of the abnormal brain regions detected on FDG-PET. The mean and SD of K trans, Ve, and CBF were calculated. Linear regression and nonparametric Spearman rank correlation analyses of K trans and Ve with CBF were performed. Dynamic contrast-enhanced curves and the area under the curve were generated for each brain region. Student t test comparisons were performed. Quantitative data revealed that patients with systemic lupus erythematosus have statistically increased K trans (P < .001) and Ve (P < .001) compared with controls. In patients with systemic lupus erythematosus, statistically significant positive correlations were seen between K trans (P < .001) and Ve (P < .001) with CBF. Furthermore, the mean area under the curve revealed statistically increased BBB permeability in the hippocampus (P = .02) compared with other brain regions in patients with systemic lupus erythematosus compared with controls. These initial findings are proof-of-concept to support the hypothesis that patients with systemic lupus erythematosus have increased BBB permeability, specifically in the hippocampus, compared with other brain regions. These findings may advance our understanding of the underlying pathophysiology affecting the brain in autoimmune diseases.

Peripheral nervous system involvement in systemic lupus erythematosus: a retrospective study on prevalence, associated factors and outcome

Despite its potentially significant impact on disease outcome, peripheral nervous system involvement in systemic lupus erythematosus has received little attention. The objective of this study was to assess the prevalence and clinical features of peripheral nervous system involvement in a large cohort of systemic lupus erythematosus patients. The records of systemic lupus erythematosus patients examined at two tertiary referral centres over a period of 14 years (from 2000 to 2014) were analyzed. Peripheral nervous system events were ascertained according to the 1999 American College of Rheumatology case definitions and by using an attribution algorithm for neuropsychiatric events. Prevalence of peripheral nervous system in systemic lupus erythematosus and demographic, clinical and laboratory features were assessed. Patients with peripheral nervous system events were compared with a control group of systemic lupus erythematosus patients without peripheral nervous system involvement. In a retrospective cohort of 1224 patients, the overall prevalence of peripheral nervous system involvement was 6.9% (85 patients, 95% confidence interval 0.06-0.08), with 68% of peripheral nervous system events attributable to systemic lupus erythematosus. Polyneuropathy was the most common manifestation observed (38 events, 39.2%), followed by cranial neuropathy in 30 cases (30.9%) and 12 cases of single (12.4%) or multiple (eight events, 8.2%) mononeuritis. The average age of systemic lupus erythematosus onset was significantly higher in patients with peripheral nervous system events than in controls (mean ± standard deviation: 45.9 ± 14.8 vs. 37.1 ± 14.0) and they were more likely to have higher SLEDAI-2K and SLICC/ACR Damage Index scores, as well as hypertension and livedo reticularis. A subgroup analysis of events deemed to be systemic lupus erythematosus-related provided similar results. Peripheral nervous system manifestations are a potential complication of systemic lupus erythematosus. Careful neurological assessment should therefore be included in the diagnostic workup of patients with systemic lupus erythematosus, especially in those with later onset and greater damage and disease activity.

Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.

SPG31 is a hereditary spastic paraplegia (HSP) caused by pathogenic variants in the REEP1 gene. The phenotype (SPG31) has occasionally been described with peripheral nervous system involvement, in additional to the gradually progressing lower limb spasticity that characterizes HSP. The objective of this study was to characterize patients with pathogenic REEP1 variants and neurophysiologically assess the extent of peripheral nerve involvement in this patient group. Thirty-eight index cases were molecular-genetically tested, yielding two previously reported pathogenic REEP1 variants and a novel missense variant, in a total of four index patients. Three of four probands and five additional family members underwent nerve conduction studies, electromyography, quantitative sensory testing, and examination of the autonomic nervous system. None of the examined patients had completely unremarkable results of peripheral nerve studies. Most showed electrophysiological signs of carpal tunnel syndrome, and one patient demonstrated a multifocal compression neuropathy. Autonomic testing revealed no severe dysfunction, and findings were limited to adrenergic function. HSP caused by pathogenic REEP1 variants may be accompanied by a generally mild and subclinical polyneuropathy with a predisposition to compression neuropathy, and should be considered in such cases.

Peripheral nervous system involvement in lymphomas.

The peripheral nervous system may be involved at any stage in the course of lymphoproliferative diseases. The different underlying mechanisms include neurotoxicity secondary to chemotherapy, direct nerve infiltration (neurolymphomatosis), infections, immune-mediated, paraneoplastic or metabolic processes and nutritional deficiencies. Accordingly, the clinical features are heterogeneous and depend on the localization of the damage (ganglia, roots, plexi, and peripheral nerves) and on the involved structures (myelin, axon, and cell body). Some clinical findings, such a focal or diffuse involvement, symmetric or asymmetric pattern, presence of pain may point to the correct diagnosis. Besides a thorough medical history and neurological examination, neurophysiological studies, cerebrospinal fluid analysis, nerve biopsy (in selected patients with suspected lymphomatous infiltration) and neuroimaging techniques (magnetic resonance neurography and nerve ultrasound) may be crucial for a proper diagnostic workup.

Neuromyositis: A Rare Extramuscular Manifestation of Dermatomyositis

Dermatomyositis (DM) and polymyositis (PM) are representative idiopathic inflammatory myopathies characterized by symmetric and progressive proximal muscle weakness. Especially, DM is identified by characteristic skin lesions and has many extramuscular manifestations including various cardiac abnormalities, interstitial lung disease, and malignancy. However, involvement of peripheral nervous system in DM/PM is very rare and less known. The term “Neuromyositis” was introduced by Senator in 1893 to describe the concomitant involvement of the peripheral nervous system in DM/PM. Since then, a very few cases of neuromyositis have been reported mainly in the United States and Europe. Therefore, the pathogenetic mechanism and disease progression are unclear. In recent years, a few more cases were reported in Asia, specifically, China and Japan; however, none in Korea. Here, we describe a case of DM-associated neuromyositis in a 42-year-old man in Korea and review previous publications through literature research. (J Rheum Dis 2019;26:211-218)

Shoshin syndrome: report of a treatable disaster

Shoshin syndrome is a rare fulminating heart failure caused by thiamine deficiency. In Japanese “sho” means acute damage and “shin” means heart. It consists of a rare and hyperacute manifestation of beriberi that was first described in polished white rice-eating communities in various locations across Asia including China, Japan and Indonesia. In a totally different context, ‘Shoshin’ is a word from Zen Buddhism meaning “beginner’s mind”, which is considered the necessary attitude to approach the Zen practice. This case report is a prime example of clinical manifestations of thiamine deficiency for the presence of both cardiological and neurological disorders, for hyperacute onset of cardiac failure (shoshin syndrome), for the simultaneous involvement of peripheral and central nervous system, and for the dramatic global recovery after thiamine replacement therapy. We therefore explain why the physician should adopt a beginner’s mind in clinical practice.

Chapter 21 - Neonatal hypotonia and neuromuscular conditions

The differential diagnosis of neonatal hypotonia is a complex task, as in newborns hypotonia can be the presenting sign of different underlying causes, including peripheral and central nervous system involvement and genetic and metabolic diseases. This chapter describes how a combined approach, based on the combination of clinical signs and new genetic techniques, can help not only to establish when the hypotonia is related to peripheral involvement but also to achieve an accurate and early diagnosis of the specific neuromuscular diseases with neonatal onset. The early identification of such disorders is important, as this allows early intervention with disease-specific standards of care and, more importantly, because of the possibility to treat some of them, such as spinal muscular atrophy, with therapeutic approaches that have recently become available.

Small fiber impairment in patients with Fibromyalgia: a neurophysiological and skin biopsy study

Fibromyalgia (FM) is a disorder of uncertain origin associated with widespread pain, tenderness, muscular spam, fatigue, sleep disturbance and cognitive dysfunction. A dysfunction of pain processing at central and peripheral level was reported. In this study we aimed to explore the presence of signs of impairment of the peripheral nervous system in a cohort of patients with FM. Fifty-one FM patients underwent Laser Evoked Potentials (LEPs) and sympathetic skin response (SSR) by the right hand, knee and foot and skin biopsy from the right thigh and right ankle. In 15 (29%) patients we found alterations of LEPs in at least two of the 3 stimulated seats (hand, knee, foot). The SSR was impaired in 15 patients by stimulation of the hand, in 9 patients for both stimulated sites. Epidermal density was reduced in 46 (90%) patients and in 41 of these there was only an interest in the proximal site. In 5 subjects (10%) neurophysiological evaluation and skin biopsy were normal. Skin biopsy in patient with FM reveals a prominent peripheral nervous system involvement in FM patients with a prevalent picture of non-length-dependent sensory neuropathy.

Peripheral nervous system involvement in systemic amyloidosis

Peripheral nervous system involvement may be a main manifestation of systemic amyloidosis or occur in the later stages of the disease in the presence of multiple organ pathology. Focal, multiple mononeuropathy, radiculopathy, polyneuropathy, autonomic nervous system dysfunction, and myopathy develop depending on the localization of amyloid deposits in the peripheral nervous system. The most characteristic symptom in systemic amyloidosis is sensorimotor polyneuropathy accompanied in most cases by the involvement of autonomic nerve fibers in the pathological process. In cases of systemic amyloidosis, peripheral nervous system involvement is progressive, leading to disability, which makes the early diagnosis of the disease and its neurological manifestations and subsequent pathogenetic therapy relevant.

Prion-related peripheral neuropathy in sporadic Creutzfeldt-Jakob disease

ObjectiveTo assess whether the involvement of the peripheral nervous system (PNS) belongs to the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease (sCJD).MethodsWe examined medical records of 117 sCJDVV2 (ataxic type), 65...

Intraepidermal Nerve Fiber Density in Friedreich's Ataxia.

Friedreich's Ataxia (FRDA) is caused by a homozygous intronic GAA expansion in the FXN gene. FRDA affects primarily the peripheral nervous system (PNS) with cumulative evidence from postmortem studies and in vitro models suggesting a developmental component of its pathology. In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs. Mean IENF density was significantly lower in FRDAs compared to controls (5.77 ± 4.68 vs 9.33 ± 1.41, p = 0.013). Clinically, cold detection threshold was decreased in FRDAs (FRDA = -3.47(-6.64; -3.14), controls = -1.71 (-3.43; -1.23), p = 0.001) while other measures of small fiber function such as warm and pain sensation thresholds did not differ from controls. Five patients had sensory complaints, but none was diagnosed with neuropathic pain at painDETECT. The degree of small fiber loss was markedly variable in our cohort and showed an inverse correlation with the GAA repeat length (R2 = 0.573, p = 0.001). Our findings support a genetically determined small fiber loss in FRDA.

Chronic Inflammatory Demyelinating Polyneuropathy in Systemic Lupus Erythematosus: A Rare Entity

Background:Neurological manifestations in Systemic Lupus Erythematous (SLE) varies and commonly affects the Central Nervous System (CNS) rather than the peripheral nervous system. Neuropsychiatric or CNS manifestation can be as high as 24-54%, whereas the peripheral nervous system involvement is lower around 5-27%. Chronic Inflammatory Demyelinating Polyradiculopathy (CIDP) is one of the three commonest peripheral nervous system involvements in SLE patients and results with severe debilitating effects. However, it is rarely reported.Methods:A retrospective review of all SLE patients that were diagnosed with CIDP between 2000 and 2015 was done under follow up at our center that were diagnosed with CIDP between 2000 and 2015. We reviewed their medical records and analyzed their clinical presentation, investigations, treatment instituted, response to therapy and any neurological sequealae.Results:A total of 512 case notes were reviewed. Of these 4 patients presented with CIDP (3 females, 1 male) aged between 26 to 46 years old. Three presented with transverse myelitis and the other one with acute motor and sensory axonal neuropathy. All patients were treated with high dose corticosteroids, three patients received cyclophosphamide whilst the other patient was induced with mycophenolate mofetil. Complete recovery was seen in one patient, two had persistent but improving numbness and the other one had a residual weakness.Conclusion:Peripheral nervous system involvement in SLE can result in serious debilitating effects. Early diagnosis and treatment are crucial in limiting the neurological sequealae.

CMT AND NEUROGENIC DISEASE: P.340Distal arthrogryposis, peripheral neuropathy and an autosomal dominant pedigree leading to a diagnosis of TRPV4-pathy

Transient receptor potential vanilloid 4 channel (TRPV4) is a calcium permeable cation channel predominantly expressed in bone and peripheral nervous system (PNS). TRPV4 mutations cause a spectrum of skeletal disorders and PNS syndromes, including Charcot-Marie-Tooth disease type 2C, spinal muscular atrophy, arthrogryposis, and scapuloperoneal spinal muscular atrophy. A 6-year-old boy from a non-consanguineous family was referred to our clinic due to arthrogryposis multiplex congenita (AMC) and weakness of lower limbs. He was not able to walk. There were six other members in the family diagnosed with varying degrees of peripheral neuropathy and short stature including his father and uncle. Physical examination showed muscle weakness in lower limbs with predominantly distal involvement and atrophy. Lower limbs were short. There were flexion contractures of knees and ankles. Deep tendon reflexes were absent in lower limbs. There was neither motor deficit in upper limbs nor cranial nerve involvement. Electromyography showed lower motor neuron involvement. Exome sequencing targeted to genes involved in arthrogryposis revealed a heterozygous mutation in TRPV4 (c.805C>T; p.Arg269Cys). This mutation is known to be pathogenic in Clinvar database (rs267607146). The mutation was confirmed by Sanger sequencing and cosegregates with the disease in the family indicating that mutation of this gene is responsible for the disease phenotype. TRPV4-pathies represent a heterogeneous group of diseases presenting with skeletal dysplasias and/or peripheral nervous system involvement. Although our patient is grouped clinically as distal SMA with arthrogryposis, there are patients who present with scapuloperoneal SMA and skeletal dysplasia harbouring the same mutation. Despite significant overlaps in presentations, distal arthrogryposis in combination with short stature, skeletal abnormalities, disproportion of upper and lower extremities and neuropathy should be clinical clues for TRPV4 mutations.

Peripheral Nervous System Involvement in Lymphoproliferative Disorders.

Peripheral neuropathies are a vast group of diseases with heterogeneous aetiologies, including genetic and acquired causes. Several haematological disorders may cause an impairment of the peripheral nervous system, with diverse mechanisms and variable clinical, electrophysiological and pathological manifestations. In this practical review, we considered the main phenotypes of peripheral nervous system diseases associated with lymphoproliferative disorders.The area of intersection of neurological and haematological fields is of particular complexity and raises specific problems in the clinical practice of lymphoproliferative disorders. The personal crosstalk between neurologists and haematologists remains a fundamental tool for a proper diagnostic process which may lead to successful treatments in most cases.

Encephalopathies with intracranial calcification in children: clinical and genetic characterization

BackgroundWe present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses.MethodsWe collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification.ResultsWe collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two.ConclusionsGenetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1.

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), caused by mutations in gap junction protein beta 1 (GJB1), is characterized by various central nervous system symptoms and gender differences of clinical severity. The aim of this study was to identify the frequency and mutation spectrum of CMTX1 patients in Japan and to demonstrate their phenotypic diversities. Using three high-throughput sequencing systems, targeted gene panel sequencing on 1483 unrelated index patients with suspected Charcot-Marie-Tooth (CMT) disease was performed. The peripheral and central nervous system involvements of all patients with GJB1 variants were assessed retrospectively and a detailed gender comparison was conducted with the CMT examination score. Twenty-three novel and 36 described GJB1 variants were identified from 88 pedigrees, in which 34 female and 78 male patients were enrolled. Mean age at onset of the male patients was much younger than the females, 21.56 ± 17.63 years vs. 35.53 ± 23.72 years (P = 0.007). Male patients presented with more severe phenotypes in every examination item, but statistical differences were observed only in motor dysfunctions of the lower extremities and vibration sensation. No significant sensory difference was identified between genders, either clinically or electrophysiologically. Central nervous system dysfunctions were found in 15 patients from 12 pedigrees. Therein, six patients developed stroke-like phenotypes, with dysarthria as the leading symptom. A relatively lower frequency of CMTX1 (5.9%) was demonstrated and a broad mutation spectrum of GJB1 was described. Detailed clinical differences between genders and various central nervous system symptoms were also illustrated, even in the same pedigree.

Unilateral Phrenic Nerve Palsy in Infants with Congenital Zika Syndrome

Abstract Since the first identification of neonatal microcephaly cases associated with congenital Zika virus infection in Brazil in 2015, a distinctive constellation of clinical features of congenital Zika syndrome has been described. Fetal brain disruption sequence is hypothesized to underlie the devastating effects of the virus on the central nervous system. However, little is known about the effects of congenital Zika virus infection on the peripheral nervous system. We describe a series of 4 cases of right unilateral diaphragmatic paralysis in infants with congenital Zika syndrome suggesting peripheral nervous system involvement and Zika virus as a unique congenital infectious cause of this finding. All the patients described also had arthrogryposis (including talipes equinovarus) and died from complications related to progressive respiratory failure.

Extra-haematological manifestations related to human parvovirus B19 infection: retrospective study in 25 adults

BackgroundTo describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection.MethodsWe conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults.ResultsData from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7–83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barré syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1), and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive, and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement.ConclusionsHPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies.