Transorbital sonography in idiopathic intracranial hypertension: Single-center study, systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Transorbital sonography (TOS) provides a noninvasive tool to detect intracranial pressure by assessing optic nerve sheath diameter (ONSD) and optic disc elevation (ODE). The utility of TOS in the diagnosis of idiopathic intracranial hypertension (IIH) has been increasingly recognized. METHODS: A single-center case-control study sought to compare TOS-acquired ONSD and ODE among IIH-cases versus patients with other neurological diseases (controls). Furthermore, a systematic review and meta-analysis was conducted to present pooled mean differences and diagnostic measures of ONSD and ODE between IIH-cases and controls. RESULTS: In the single-center study, consisting of 31 IIH-cases and 34 sex- and age-matched controls, ONSD values were higher among IIH-cases than controls (p<.001), while ODE was more prevalent in cases (65% vs. 15%; p<.001). The receiver-operating characteristic (ROC)-curve analysis revealed that the optimal cutoff value of ONSD for predicting IIH was 5.15 mm, with an area under the curve (AUC) of 0.914 (95% confidence interval [CI]: 0.861-0.967) and sensitivity and specificity values of 85% and 90%, respectively. In a meta-analysis of 14 included studies with 415 IIH-cases, ONSD and ODE values were higher in IIH-cases than controls (mean difference in ONSD 1.20 mm; 95% CI: 0.96-1.44 mm and in ODE 0.3 mm; 95% CI: 0.33-0.67 mm). With regard to ONSD, pooled sensitivity, specificity, and diagnostic odds ratio were calculated at 85.5% (95% CI: 77.9-90.8%), 90.7% (95% CI: 84.6-94.5%), and 57.394 (95% CI: 24.597-133.924), respectively. The AUC in summary ROC-curve analysis was 0.878 (95% CI: 0.858-0.899) with an optimal cutoff point of 5.0 mm. CONCLUSIONS: TOS has a high diagnostic utility for the noninvasive diagnosis of IIH and may deserve wider implementation in everyday clinical practice.

Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

Oculomotor nerve palsy as an extraintestinal manifestation of Crohn's disease.

Patients with inflammatory bowel disease (IBD) may present with extraintestinal manifestations. Neurological symptoms associated with IBD are infrequent. Thus, any unexplained neurological symptom that occurs in patients with IBD should raise the suspicion of a link between the two disorders. We report a case of a man in his 60s, who was diagnosed with Crohn's disease and developed ptosis and diplopia. Neurological examination revealed oculomotor nerve palsy, sparing the pupil. MRI and magnetic resonance angiography of the brain were insignificant and no other cause was determined. He was treated with oral corticosteroids and symptoms gradually subsided. Cranial nerve palsies associated with IBD have been rarely reported. They usually involve the optic and acoustic nerve and are attributed to a common dysimmune base. This is the first reported case of oculomotor nerve palsy (III cranial nerve) associated with IBD. Clinicians treating patients with IBD should be alert for unusual neurological complications and treat them appropriately.

Impaired cerebral autoregulation in Fabry disease: A case-control study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls. METHODS: TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated. RESULTS: Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities. CONCLUSIONS: Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls.

Non-pharmacological Interventions on Pain and Quality of Life in Chemotherapy Induced Polyneuropathy: Systematic Review and Meta-Analysis.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN. MATERIALS AND METHODS: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol. RESULTS: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant. CONCLUSION: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms.

Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. OBJECTIVE: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. METHODS: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. RESULTS: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. CONCLUSION: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (GLA) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated. METHODS: We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y-positive patients, and (3) the proportion of D313Y-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). RESULTS: Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I2 = 34%) and 16.2% (95% CI 8%-26.4%; I2 = 35%) of cases, respectively. D313Y-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I2 = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I2 = 51%) and 28.5% (95% CI 17.8%-40.5%; I2 = 61%) of cases, respectively. DISCUSSION: D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify D313Y-positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.

Neurophysiological and ultrasonographic comparative study of autonomous nervous system in patients suffering from fibromyalgia and generalized anxiety disorder.

BACKGROUND: Fibromyalgia (FM) and generalized anxiety disorder (GAD) share common clinical features: they both affect women more than men, their diagnosis is based solely on clinical criteria, and some of the symptoms such as anxiety, aches and muscle tension, sleep disorders, and cognitive dysfunction occur in both diseases. For both conditions, an underlying dysregulation of the autonomic nervous system (ANS) has been proposed. OBJECTIVE: The aims of this study were to investigate ANS dysfunction in FM and GAD and compare them with controls. METHODS: Sympathetic skin response (SSR) from palm and sole and cross-sectional area (CSA) of bilateral vagus nerves (VN) were measured in 28 healthy controls, 21 FM patients, and 24 GAD patients. RESULTS: CSA of VN was significantly smaller in FM patients (right: 1.97 ± 0.74mm2, left: 1.75 ± 0.65 mm2) and GAD patients (right: 2.12 ± 0.97mm2, left: 1.71 ± 0.86 mm2) compared to controls (right: 3.21 ± 0.75 mm2, left: 2.65 ± 1.13 mm2, p < 0.001, but did not differ between the two patient groups. SSR parameters were similar between patients and controls. SSR latency correlated to clinical scales (FM Widespread Pain Index) in the FM group (r = 0.515, p = 0.02 and r = 0.447, p = 0.05) for the upper and lower limbs respectively, but no other correlation between clinical and neurophysiological parameters was identified. CONCLUSION: This study confirms similar ANS abnormalities in FM and GAD that fairly distinguish them from controls and support the hypothesis of a common pathophysiological substrate underlying both conditions.

The Effect of Neuromuscular Electrical Nerve Stimulation in the Management of Post-stroke Spasticity: A Scoping Review.

Stroke is a cerebrovascular disorder characterized by the sudden onset of symptoms and clinical signs caused by either vascular infraction or hemorrhage. One of the main symptoms in the majority of post-stroke patients is spasticity. The main therapeutic options of spasticity in post-stroke patients include pharmacological interventions, rehabilitation techniques, and surgery. This review aims to explore the effectiveness of Neuromuscular Electrical Stimulation (NMES) for post-stroke spastic hemiparetic limb (upper and lower). Thorough research of the PubMed Medline database was performed. Records were limited to clinical studies published between 01/01/2010 and 01/01/2022. The results were screened by the authors in pairs. The search identified 26 records. After screening, nine records met the inclusion-exclusion criteria and were assessed. There were seven studies for spastic upper limbs and two for spastic lower limbs. The approaches investigated the effectiveness of electrical stimulation on post-stroke spastic upper or lower limb. Spasticity was measured through the modified Ashworth scale (MAS) and electromyographic recordings (EMG). In most cases, spasticity was decreased for at least two weeks post-intervention. In conclusion, NMES can be used either solo or in combination with different physical therapy modalities in order to produce optimal results, taking into consideration the specific needs and limitations of each individual patient. Based on the existing literature, as well as the limitations of the included studies, the authors believe that future studies on the subject of NMES in the management of post-stroke spasticity should focus on carefully examining each electrical parameter.

An uncommon variant of fibromuscular dysplasia.

Fibromuscular dysplasia is a rare cause of stroke affecting mostly young females. It is characterized by the typical "string of beads" sign located mostly bilaterally in the midcervical portion of the carotid or vertebral arteries. We present the uncommon case of borderzone hemispheric infarction in a man with isolated unilateral fibromuscular dysplasia affecting continuously the distal extracranial and proximal intracranial portion of the left internal carotid artery leading to distal hypoperfusion and ischemia.

Intraoperative radial nerve injury during coronary artery surgery--report of two cases.

BACKGROUND: Peripheral nerve injury and brachial plexopathy are known, though rare complications of coronary artery surgery. The ulnar nerve is most frequently affected, whereas radial nerve lesions are much less common accounting for only 3% of such intraoperative injuries. CASE PRESENTATIONS: Two 52- and 50-year-old men underwent coronary artery surgery. On the first postoperative day they both complained of wrist drop on the left. Neurological examination revealed a paresis of the wrist and finger extensor muscles (0/5), and the brachioradialis (4/5) with hypoaesthesia on the radial aspect of the dorsum of the left hand. Both biceps and triceps reflexes were normoactive, whereas the brachioradialis reflex was diminished on the left. Muscles innervated from the median and ulnar nerve, as well as all muscles above the elbow were unaffected. Electrophysiological studies were performed 3 weeks later, when muscle power of the affected muscles had already begun to improve. Nerve conduction studies and needle electromyography revealed a partial conduction block of the radial nerve along the spiral groove, motor axonal loss distal to the site of the lesion and moderate impairment in recruitment with fibrillation potentials in radial innervated muscles below the elbow and normal findings in triceps and deltoid. Electrophysiology data pointed towards a radial nerve injury in the spiral groove. We assume external compression as the causative factor. The only apparatus attached to the patients' left upper arm was the sternal retractor, used for dissection of the internal mammary artery. Both patients were overweight and lying on the operating table for a considerable time might have caused the compression of their left upper arm on the self retractor's supporting column which was fixed to the table rail 5 cm above the left elbow joint, in the site where the radial nerve is directly apposed to the humerus. CONCLUSION: Although very uncommon, external compression due to the use of a self retractor during coronary artery surgery can affect--especially in obese subjects--the radial nerve within the spiral groove leading to paresis and should therefore be included in the list of possible mechanisms of radial nerve injury.

Cerebral Whipple's disease diagnosed using PCR: the first case reported from Greece.

BACKGROUND: Whipple's disease (WD) is a rare multisystemic bacterial infection, with variable clinical manifestations occasionally involving the central nervous system. As the cultivation of the etiologic agent, Tropheryma whippelii, is difficult, a laboratory diagnosis is usually based on histological methods. In the last few years, molecular detection of the bacterial 16SrRNA genes by PCR, with 2 primer sets, has greatly contributed to the ability of clinicians to diagnose this disease. We present a cerebral case of WD in a 48-year-old male, successfully diagnosed using PCR with T. whippelii in the blood and feces. As far as we know this is the first case reported from Greece. METHODS: For the diagnosis of WD, histological examination of duodenum biopsy for diastase-resistant, non-acid fast, periodic acid Schiff (PAS)-positive inclusions in macrophages, and molecular detection of the 16SrRNA genes of T. whippelii by PCR in cerebrospinal fluid, blood, and feces, were performed. RESULTS: The histological detection was negative. PCR results were positive in the blood and feces of the patient and negative in the cerebrospinal fluid. Seven months after the onset of antimicrobial therapy, PCR was negative in all three clinical specimens. CONCLUSIONS: The application of PCR proved to be an invaluable tool for the recognition, differential diagnosis and early initiation of antimicrobial therapy for the patient diagnosed with WD, a disease which is generally fatal if it remains untreated.