ANCA-associated vasculitis presenting with isolated neurological manifestations in a patient with cocaine abuse: a case report and literature review.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare conditions predominantly affecting small vessels of skin, musculoskeletal, pulmonary, renal, and rarely central and peripheral nervous systems. Isolated neurological manifestations of AAV are uncommon and challenging to diagnose. Cocaine has been reported as a potential trigger for the development of AAV. There are only a few case reports of isolated neurological involvement in cocaine-induced AAV with poorly characterized histopathological features. We present a unique case of AAV with isolated neurological manifestations presenting with multiple cranial neuropathies, leptomeningeal enhancement on imaging and histopathologic evidence of small-vessel vasculitis in the leptomeninges and brain and extensive dural fibrosis in a patient with cocaine abuse. The patient's progressive neurological deficits were controlled after starting immunosuppression with rituximab and prednisone. We also reviewed the literature to provide the diagnostic overview of AAV and evaluate intervention options. To our knowledge, this is the first case of AAV with isolated neurological manifestations and histopathologic evidence of small-vessel vasculitis in a patient with cocaine abuse. Patients with multiple cranial neuropathies and meningeal involvement should be screened for AAV, especially if they have a history of cocaine abuse.

Retrospective review of patients with myasthenia gravis switched from plasma exchange therapy to efgartigimod treatment.

INTRODUCTION/AIMS: Therapeutic plasma exchange (TPE) is sometimes used as maintenance therapy for the treatment of myasthenia gravis (MG). Efgartigimod is a newly approved monoclonal antibody targeting the neonatal Fc receptor, effectively reducing immunoglobulin G levels in the treatment of MG. The aim of this study was to describe the clinical experience of switching patients from maintenance TPE treatment to efgartigimod infusions. METHODS: A retrospective review of medical records was performed on patients previously treated with maintenance TPE for the diagnosis of MG and subsequently switched to efgartigimod infusions. Clinical characteristics and response to treatment switch were described. RESULTS: Five of seven patients demonstrated improvement on Myasthenia Gravis Foundation of America-post intervention status, one was unchanged and one was in pharmacological remission. This was reflected in pre- and postswitch MG activities of daily living and MG manual muscle testing scores. All patients have continued on efgartigimod therapy. The duration of treatment with efgartigimod at the time of this review ranged from 1 to 13 months. Recurrent uncomplicated infections were noted in two patients on efgartigimod therapy. Maintenance dosing regimens of efgartigimod varied based on clinical response to treatment and side effects. DISCUSSION: In this series, efgartigimod appeared effective and well tolerated in patients switched from TPE.

Disease-Based Prognostication: Myasthenia Gravis.

Myasthenia gravis (MG) is an acquired autoimmune neuromuscular junction transmission disorder that clinically presents as fluctuating or persistent weakness in various skeletal muscle groups. Neuroprognostication in MG begins with some basic observations on the natural history of the disease and known treatment outcomes. Our objective is to provide a framework that can assist a clinician who encounters the MG patient for the first time and attempts to prognosticate probable outcomes in individual patients. In this review article, we explore clinical type, age of onset, antibody status, severity of disease, thymus pathology, autoimmune, and other comorbidities as prognostic factors in MG.

Bilateral Acute Hippocampal Ischemia in Two Patients Abusing Cocaine: What is the Outcome?

Hippocampal ischemia is a rare complication of cocaine abuse that has been thought to arise from vasospasm, anoxic injury, and/or catecholaminergic excitotoxicity. We present two cases of patients abusing cocaine, who presented with an acute onset anterograde amnesia due to bilateral hippocampal ischemia, and had different outcomes. Case 1 is a 49-year-old male with a history of IV heroin abuse who presented after being found down for an unknown period of time. He awoke with no memory of events leading up to hospitalization and was unable to retain new information. Urine toxicology was positive for cocaine and opiates. Traditional vascular risk factors included obesity, hypertension, and hyperlipidemia. His recovery was complicated by continued drug use and one episode of cardiac arrest. Despite cognitive rehabilitation, only minimal improvements in his anterograde memory were observed during his annual follow-up. Case 2 is a 23-year-old male with a history of attention deficit disorder treated with dexmethylphenidate and a history of consistent marijuana and cocaine abuse, who presented with nausea, vomiting, chest pain, shortness of breath, and acute-onset short-term memory loss. Urine toxicology was negative for cocaine and opiates and positive for marijuana. He had no known vascular risk factors. With cognitive rehabilitation and discontinuation of illicit drug use, he demonstrated a significant improvement in his memory function over the course of six months. Brain MRI in both patients showed symmetric bilateral hippocampal diffusion restriction without post-contrast enhancement with corresponding hyperintensities on fluid-attenuated inversion recovery sequences. In both patients, cerebrospinal fluid (CSF) studies were unremarkable for inflammation or infection, and electroencephalograms were normal in awake and drowsy states. Bilateral hippocampal ischemia should be considered as a potential cause of acute onset anterograde amnesia in patients with a history of cocaine abuse. Other substances such as heroin and dexmethylphenidate may potentially increase susceptibility for hippocampal ischemia in patients using cocaine. Discontinuation of illicit drug abuse can influence the degree of recovery from acute bilateral hippocampal ischemia.

A Case of MuSK Myasthenia Gravis Presenting With Persistent Respiratory Insufficiency.

ABSTRACT: Muscle-specific kinase (MuSK) antibody is seen in 4%-10% of patients with myasthenia gravis (MG), with 40% of these patients reporting bulbar weakness as the initial symptom. We present the case of a 40-year-old woman with MuSK MG whose only presenting symptom was progressive respiratory insufficiency necessitating BiPAP use 16-24 hours daily. She was unresponsive to treatment for cardiac and pulmonary causes and thus referred to neurology. Initial workup directed toward autoimmune and genetic myopathies was unrevealing. MuSK antibodies were positive (60.7 nmol/L, nl 0.00-0.02). Electrodiagnostic studies were unremarkable other than single fiber electromyography which was consistent with a defect in neuromuscular transmission. Treatment with prednisone, plasma exchange, and rituximab led to improvement to reliance on BiPAP only at night. However, her most treatment refractory and quality of life limiting symptom continues to be respiratory insufficiency. Further investigation to better characterize differential response to treatment in this subset of patients with MuSK MG may be needed.

Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation.

Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.

Tactile experience does not ameliorate age-related reductions in sensory function.

UNLABELLED: BACKGROUND/STUDY CONTEXT: Sensory function degrades with age, with well-established reductions in tactile spatial acuity, vibrotactile sensitivity, and thermosensation, to name but three aspects of perception. Such age-related losses might be partially stemmed by ongoing experience with tasks requiring high levels of manual dexterity or analogous tactile expertise; individuals who are highly expert in skills that have a fundamental tactile component can show improved tactile function as compared with nonexperts. METHODS: Eighty individuals (17 males, 63 females) in the 18-58 age range were assessed on their tactile experience, as measured by self-assessment on a variety of tasks and competencies, each of which required a high level of skill with the hands. Tactile sensory performance, manual dexterity ("haptic efficiency"), and the subjective response to tactile stimulation were quantified. RESULTS: Degradation in tactile sensory acuity with age was confirmed, but no strong evidence was found for variations in acuity contingent on the tactile expertise of participants. In contrast to the performance measures, differences in tactile experience were associated with differences in the subjective response to touch. Greater tactile experience was associated with the provision of richer descriptions of textured materials manipulated with the digits. CONCLUSION: The range of tactile experience reported in a convenience sample of the population was apparently insufficient to preserve sensory function during aging.

Effect of hydration on the tactile and thermal sensitivity of the lip.

The vermilion lip is a body site particularly susceptible to water loss. Therefore, the role of hydration in tactile perception at the lip was investigated. A series of measures of tactile performance and response were obtained from 22 female subjects, namely: (1) the subjective assessment of lip feel, (2) tactile sensitivity, (3) spatial acuity, (4) thermal sensitivity, and (5) the subjective assessment of thermal stimulation. These measures were obtained from lips in their natural (untreated) state, and lips that had been treated using a hydrating preparation. The preparation altered the subjective feel of the lips consistent with the treatment increasing lip hydration and compliance. Hydrated lips showed greater sensitivity to light touch, and there was a trend toward the lip's thermal sensitivity being altered consistent with the lip treatment having a physical cooling effect. Spatial acuity was unaltered by the state of lip hydration. The sensitivity changes on hydration were proposed to have mechanical basis.

Perception of fluids with diverse rheology applied to the underarm versus forearm skin.

Little is known about the tactile-perceptual structure of fluids. Therefore, ten fluids with diverse, characterized rheologies were rated by 16 females, on 27 sensory attributes (e.g., "slippery") and 14 emotional attributes (e.g., "enjoyable") via five-point categorical scales. Fluids were assessed against the volar forearm and underarm, sites that commonly experience contact with fluids during the use of personal care products. Application of fluids was either by the participant to their own body ("self-applied") or by the experimenter to the participant's body ("experimenter-applied"). Separate factor analyses of the sensory and emotional attributes for different body sites and modes of touch suggested approximately the same factorial structure in each case. Four general sensory factors emerged, labeled Lubricating, Textured, Silken, and Viscous, and two emotional factors, Comfortable and Arousing. These factors resembled those from equivalent work that used solid materials as stimuli, emphasizing that despite the differences in perceptual structure between fluid-coated and dry, solid surfaces, different body sites, and modes of touch influence the perception of fluid and dry stimuli similarly. As expected, fluids varied widely in how they scored on the factors. Site-wise differences were found, whereby stimuli assessed against the forearm were rated as more Lubricating, less Textured, more Silken, and more Comfortable than they were against the underarm. Self-applied touch was less Comfortable than experimenter-applied. The physical and perceptual were linked insofar as greater measured viscosity at low shear rates was associated with perceptions of cold and wet, whereas at high shear rates, greater viscosity was associated with greater perceived thickness.

Tactile and thermal detection thresholds of the scalp skin.

The tactile and thermal sensitivity of diverse regions of the human body have been documented extensively, with one exception being the scalp. Additionally, sensory changes may accompany the hair loss from the scalp in androgen-related alopecia (ARA), but formal quantitative sensory testing (QST) has not been reported in respect of this. Therefore, light touch detection thresholds were obtained at nine scalp sites and one forehead site, using Semmes-Weinstein filaments (Von Frey hairs), and for warming and cooling from skin baseline temperature, using 28 and 256 mm(2) thermodes. Affective, thermal, and nociceptive sensations experienced at thermal detection threshold were quantified. Thirty-two male participants were recruited, 10 of whom had normal hair coverage, 12 of whom had shaved scalp but with potentially normal hair coverage, and 10 of whom exhibited ARA to some extent. The scalp was relatively insensitive to tactile and thermal stimulation at all tested sites, especially so along the midline and near the apex of the skull. Threshold level warm stimuli were rated less pleasant, the less sensitive the test site. After correction for age-related changes in sensitivity, bald scalp sites were found more sensitive to cooling than the same sites when shaved, consistent with prior informal reports of increased sensitivity for some scalp sensations in ARA. QST on hair-covered sites was subject to methodological issues that render such testing non-ideal, such as bias in measurement of resting skin temperatures, and the near impossibility of delivering filament stimuli to the scalp skin without disturbing neighboring hairs.

The development and validation of sensory and emotional scales of touch perception.

No comprehensive language exists that describes the experience of touch. Three experiments were conducted to take steps toward establishing a touch lexicon. In Experiment I, 49 participants rated how well 262 adjectives described sensory, emotional and evaluative aspects of touch. In Experiment II, participants rated pairwise dissimilarities of the most descriptive words of the set. Multidimensional scaling (MDS) solutions representing semantic-perceptual spaces underlying the words resulted in a touch perception task (TPT) consisting of 26 'sensory' attributes (e.g., bumpiness) and 14 'emotional' attributes (e.g., pleasurable). In Experiment III, 40 participants used the TPT to rate unseen textured materials that were moved actively or received passively against the index fingerpad, volar forearm, and two underarm sites. MDS confirmed similar semantic-perceptual structures in Experiments II and III. Factor analysis of Experiment III data decomposed the sensory attribute ratings into factors labeled Roughness, Slip, Pile and Firmness, and the emotional attribute ratings into Comfort and Arousal factors. Factor scores varied among materials and sites. Greater intensity of sensory and emotional responses were reported when participants passively, as opposed to actively, received stimuli. The sensitivity of the TPT in identifying body site and mode of touch-related perceptual differences affirms the validity and utility of this novel linguistic/perceptual tool.

Small fiber neuropathy is associated with the metabolic syndrome.

BACKGROUND: The etiology of sensory neuropathies is often not found. We tested the hypothesis that the metabolic syndrome (MS) may be associated with painful neuropathy, in the absence of frank diabetes. METHODS: Clinical and quantitative neuropathy assessments were performed on 10 neuropathy patients with MS, 20 with MS with type 2 diabetes (10 recent onset and 10 of >5 years in duration), and 10 healthy, age-matched subjects. Intraepidermal nerve fiber density (IENF) and mean dendrite length (MDL) were determined by quantitative immunofluorescence on skin biopsies using antibody to PGP 9.5. RESULTS: In metabolic syndrome, MDL was reduced and correlated negatively with sensory symptoms, signs, HDL-C, and sural nerve amplitude. The strongest inverse metabolic correlate of the metabolic syndrome neuropathy was HDL-C, which also correlated negatively with sensory symptoms, signs, and sural nerve amplitudes. The strongest metabolic correlate of diabetic sensorimotor neuropathy was HbA1c, which was associated with reduced IENF in patients with >5 years in duration of disease as well as reduced peroneal nerve amplitudes. CONCLUSIONS: These data indicate that metabolic features, including HDL-C in metabolic syndrome, are associated with small fiber neuropathy and that MDL is an early marker of sensory neuropathy in patients with MS. Reductions in IENF reflect a longer duration of diabetes, with hyperglycemia leading to a sensorimotor neuropathy. These findings support the possibility that there is a sensory neuropathy with reduced intraepidermal nerve fiber length, which cosegregates with features of metabolic syndrome.

Diabetic neuropathies.

Diabetic neuropathy (DN) is a common complication of diabetes that often is associated with considerable morbidity and mortality. The epidemiology and natural history of DN is clouded with uncertainty because of confusion regarding the definition and measurement of this disorder. The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis,and the possibility of the role of autoimmunity has opened up new avenues of investigation for therapeutic intervention. The ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on success in uncovering the pathogenic processes underlying this disorder.

Diagnosis and management of diabetic autonomic neuropathy.

Autonomic neuropathy affects every system in the body including the eye, cardiovascular, respiratory, and gastrointestinal and neurovascular systems. The diagnosis confers an attenuated life expectancy, but much can be done to alleviate symptoms and to address the underlying disorder.