Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies.

OBJECTIVES: To demonstrate treatment efficacy on composite and non-length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%-55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial. METHODS: In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores. RESULTS: Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002). CONCLUSIONS: IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.

Immune-Mediated Small Fiber Neuropathy With Trisulfated Heparin Disaccharide, Fibroblast Growth Factor Receptor 3, or Plexin D1 Antibodies: Presentation and Treatment With Intravenous Immunoglobulin.

OBJECTIVES: Up to 50% of small fiber neuropathy (SFN) cases are idiopathic, but novel antibodies to Trisulfated Heparin Disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been implicated in half of these cases; the role of anti-Plexin D1 is less clear. We aimed to clarify presentation and management of these patients. METHODS: An 18-month retrospective analysis revealed 54 cases of cryptogenic SFN who had testing for the 3 autoantibodies. Demographics, clinical features, epidermal nerve fiber density, and Quantitative Sudomotor Axon Reflex Test results were analyzed. Intravenous immunoglobulin (IVIG) treatment response was assessed. RESULTS: In total, 44.4% of patients had antibodies (62.5% TS-HDS, 29.2% FGFR-3, and 20.8% Plexin D1). Male patients were more likely to be FGFR-3 positive (P = 0.014). Facial involvement was more common in seropositive patients (P = 0.034), and patients with a higher Utah Early Neuropathy Scale score had a higher TS-HDS titer (P = 0.0469), but other clinical features were not significantly different. Seropositive patients trended toward a higher SFN screening list score (P = 0.16), abnormal Quantitative Sudomotor Axon Reflex Test (P = 0.052), and prior erroneous diagnosis (P = 0.19). In patients who completed IVIG, examinations and questionnaires improved and mean epidermal nerve fiber density increased by 297%. CONCLUSIONS: TS-HDS, FGFR-3, and Plexin D1 antibodies are present in a high proportion of cryptogenic SFN cases with more facial involvement, and greater disease severity is associated with higher antibody titers. They are often misdiagnosed but may respond subjectively and objectively to IVIG.

Clinical Features and Treatment Response in Immune-Mediated Small Fiber Neuropathy with Trisulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies.

OBJECTIVE: Novel antibodies to trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been recently described in otherwise cryptogenic small fiber neuropathy (SFN) cases. Our goal was to further describe clinical features in such cases and to analyze treatment responses. METHODS: In a retrospective analysis, 40 cases of cryptogenic SFN in a university neuropathy clinic were identified. Of these, TS-HDS and FGFR-3 cases were identified, and clinical features and treatment responses were analyzed. RESULTS: In this cohort, 95% were women, and 55% had either TS-HDS or FGFR-3 antibodies (77% of these had TS-HDS). Of the seropositive group, 41% had a nonlength dependent epidermal nerve fiber density on skin punch biopsy (OR = 1.80). In the seropositive group, 82% had neuropathic pain as their primary symptom (OR = 1.73). Also 32% of seropositive patients reported widespread pain (OR = 1.63). 63% of seropositive cases presented acutely (OR = 11.0). In the seropositive group, 23% had an initial erroneous diagnosis (OR = 1.47). Eight seropositive patients improved on intravenous immunoglobulin treatment, with a 42% reduction in pain scores (P = 0.02), a 44% reduction in the Utah Neuropathy Score, and improved epidermal nerve fiber density post-treatment. CONCLUSIONS: TS-HDS and FGFR-3 antibodies may be present in a high proportion of cryptogenic SFN cases with acute onset, nonlength dependent pathology, and primary neuropathic and widespread pain. They are often misdiagnosed as other conditions including fibromyalgia. These cases may be responsive to immune treatment, especially with intravenous immunoglobulin.

Advances in the Management of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) is a prevalent neurologic syndrome. Testing methods have emerged in recent years to better diagnose it, including autonomic tests and skin punch biopsy. SFN can present in a non-length-dependent fashion and can be mistaken for syndromes such as fibromyalgia and complex regional pain syndrome. SFN is caused by a variety of metabolic, infectious, genetic, and inflammatory diseases. Recently treatments have emerged for TTR amyloid neuropathy and Fabry disease, and novel biomarkers have been found both in genetic and inflammatory SFN syndromes. Ongoing trials attempt to establish the efficacy of intravenous immunoglobulin in inflammatory SFN syndromes.

An electrodiagnostic grading system for ulnar neuropathy at the elbow.

INTRODUCTION: Ulnar neuropathy at the elbow (UNE) is the second most common entrapment neuropathy. Our goal was to create and analyze a grading system for UNE electrodiagnostic severity. METHODS: We retrospectively analyzed EMG reports with UNE. We then classified 112 limbs as having mild, moderate, or severe grade UNE based on electrodiagnostic findings. The association between presenting symptoms and signs, EMG findings, treatment type, and electrodiagnostic grade was statistically analyzed. RESULTS: Seventeen limbs (15.2%) had mild, 80 (71.4%) had moderate, and 15 (13.4%) had severe UNE. Symptoms (P = .016), exam findings (P < .001), and treatment type (P = .043) were significantly associated with electrodiagnostic grade. DISCUSSION: Our UNE grading system was significantly related to symptoms, physical exam, and treatment selection and may be useful to measure electrodiagnostic severity.

Haven or Limbo? Neuroscientist Refugees From National Socialism Escape to Illinois.

At least 9 neuroscientists immigrated from Nazi Europe to Illinois to escape tyranny and attempt to re-establish their careers. Some work has been published in print on eponymous neuroscientist Adolf Wallenberg, as well as 2 others but not on Ernst Haase, Frederick Hiller, Erich Liebert, Bruno Volk, Heinz (Henry) von Witzleben, or Gerhard Pisk. Before leaving Germany or Austria, these downtrodden specialists were dismissed from long-held posts sometimes for trumped-up charges, stripped of their financial security, and forced to leave relatives behind. At least 1 left only for personal and political, but not because of racial, reasons. Illinois, in exemplary fashion, welcomed these unfortunate survivors more than many other states because of limited licensing requirements, numerous opportunities at state hospitals, and special internship programs. Some of them successfully continued their research agendas and published, taught neurology students and trainees, and added to the expansion of neurologic care in Illinois or elsewhere, but most of them took years to reacquire the academic rank they lost and never regained their career momentum. These refugees survived and passed on some of their extensive training and expertise to a new generation of neuroscientists in America, but not without significant cost.

Cryptogenic small-fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor-3.

INTRODUCTION: Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. METHODS: One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. RESULTS: Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. DISCUSSION: Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.

Fisher-Pharyngeal-Cervical-Brachial Overlap Syndrome With Novel Ganglioside Antibodies.

Several variants of Guillain-Barré syndrome have been described. The Fisher syndrome (FS) presents with ataxia, areflexia, and ophthalmoparesis. The pharyngeal-cervical-brachial (PCB) variant presents with bulbar weakness, along with arm and neck weakness. The 2 variant syndromes can overlap. Both the isolated and overlap syndromes respond to immunomodulatory treatment, thus are important to recognize clinically. Ganglioside antibodies are detectable in the variant syndromes and may aid in their diagnosis. The FS typically is associated with anti-GQ1b antibodies, and PCB is typically associated with anti-GT1a antibodies, whereas the overlap syndrome may have both ganglioside antibody subtypes. We present a case of overlap FS-PCB syndrome with a novel ganglioside antibody profile of GM1 and GD1b antibodies, which typically are associated with other variant syndromes. This case suggests the need for all ganglioside antibodies to be tested in suspected variant Guillain-Barré syndromes. The antibodies may prove especially useful in cases in which the clinical diagnosis is ambiguous.

A carpal tunnel grading system including combined sensory index-diagnosed mild cases: Relation to presenting features and outcomes.

INTRODUCTION: Prior studies have demonstrated superiority of the combined sensory index (CSI) algorithm in diagnosing mild carpal tunnel syndrome (CTS) and have compared presenting symptoms to CTS grade. However, CTS symptoms, signs, and outcomes, including CSI-diagnosed cases, have not been compared with CTS grade. METHODS: We retrospectively studied 294 CTS hands from 2010 to 2013; stratified them into mild, moderate, and severe grades; and analyzed the association between CTS grade and presenting symptoms/signs and outcomes. RESULTS: Sensorimotor symptoms (P = 0.017) and signs (P < 0.001) were significantly associated with CTS grade. Regardless of CTS grade, 94% of hands improved with surgery compared with 42% with conservative treatment (P < 0.001). Even in mild CTS, 100% improved with surgery vs. 33% with conservative management (P = 0.011). DISCUSSION: These results corroborate prior studies that compared symptoms to CTS grade and suggest that more objective signs associate even better. CTS grades associate with outcomes, but additional studies are required. Muscle Nerve 57: 45-48, 2018.

Hans Jacob and brain research on Hamburg "euthanasia" victims: "Awaiting further brains!"

Several neuropathologists conducted brain research on victims of so-called euthanasia programs carried out by the National Socialist (Nazi) regime in Germany from 1940 to 1945. Some published their results in German journals or books during and after the war. One of these neuropathologists was Hans Jacob of Hamburg, a former Nazi party member and the leader of the same laboratory previously run by Alfons Jakob (Creutzfeldt-Jakob disease). Though much has been published on the unethical actions of Jacob's fellow neuropathologist from Berlin, Julius Hallervorden, Jacob's actions were remarkably similar and have not been previously analyzed in the neuroscience literature. Jacob dissected at least 42 patient brains from euthanasia centers near Hamburg, and saved the specimens from at least 17 of them. He published a 1956 book chapter featuring 2 such specimens. Jacob was denazified, had a notable career, and never publicly addressed his actions during the war. His ethical violations may not have been on the same scale as Hallervorden's, but the effect of his work echoes to the modern era. As responsible researchers, we must always be conscious of the provenance of material provided and not succumb to opportunistic temptation despite the ethical consequences.

The Central Role of Neuroscientists under National Socialism.

Neuroscientists played central roles in the victimization of colleagues and their patients during the era of National Socialism from 1933 to 1945. After helping dismiss Jewish and nonideologically aligned colleagues, German neuroscientists were among the physicians and researchers who joined the Nazi Party and affiliated groups in record numbers. Forced sterilization and then so-called 'euthanasia' of neurological and psychiatric patients were planned and executed by prominent German and Austrian neuroscientists. Other neuroscientists collaborated indirectly by using patients for unethical experimentation to discover the cause of multiple sclerosis or to try to induce epileptic convulsions in a hypoxic state. Some merely used neuropathological material from murdered patients for publications in scientific journals. In the totalitarian state, research funding and academic advancement were awarded to physicians engaged in eugenics research. Opportunism and ideologically tainted science without regard to medical ethics were the motivating factors for collaborating neuroscientists. Some German and Austrian neuroscientists tried to resist Nazi policies, although much more passively than their colleagues in German-occupied countries. French, Dutch, Norwegian, and Danish neuroscientists actively resisted the Nazification of their profession from the beginning and helped to save some patients and colleagues, at great personal risk. Many German, Austrian, Czech, and Polish neurologists were murdered in the Holocaust, and hundreds of thousands of neurological and psychiatric patients were sterilized or murdered in just 12 years. The Nazis used the 'successful' techniques developed in the 'euthanasia' programs to carry out the mass murder of millions in the Holocaust. Today's neuroscientists are obligated to learn of the ethical violations of their predecessors 70-80 years ago. No law will prevent abandonment of the basic principles of ethical patient care and professionalism that can occur in any totalitarian state, but neuroscientists can possibly prevent it.