Diagnosis and treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States: Recommendations from a panel of experts.

Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.

Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: A 25-year longitudinal study.

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

Optimizing the operation of an electrodiagnostic laboratory during the COVID-19 pandemic: A 6-month single-center experience.

INTRODUCTION/AIMS: The initial surge of the coronavirus disease-2019 (COVID-19) pandemic in early 2020 led to widespread cancellation of elective medical procedures in the United States, including nonurgent outpatient and inpatient electrodiagnostic (EDx) studies. As certain regions later showed a downtrend in daily new cases, EDx laboratories have reopened under the guidance of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). In our reopening experience guided by the AANEM, we measured relevant outcomes to determine further workflow adaptations. We aimed to detail our experience and share the lessons learned. METHODS: We reviewed the clinical volumes, billing data, diagnosis distributions, and rates of COVID-19 exposure and transmission among patients and staff in our EDx laboratory during the first 6 months of reopening, starting on June 1, 2020. For context, we detailed the recent AANEM guidelines we adopted at our laboratory, supplemented by other consensus statements. RESULTS: We completed 816 outpatient studies from June 1 to December 1, 2020, reaching 97% of the total volume and 97% of total billing compared with the same time period in 2019. The average relative value units per study were similar. There were no major shifts in diagnosis distributions. We completed 10 of 12 requested inpatient studies during this period. There were no known COVID-19 transmissions between patients and staff. DISCUSSION: Our experience suggests that it is possible to safely operate an EDx laboratory under the guidance of the AANEM and other experts, with clinical volume and billing rates comparable to pre-pandemic baselines.

Development and validation of an interpretable deep learning framework for Alzheimer's disease classification.

Alzheimer's disease is the primary cause of dementia worldwide, with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and MRI to identify likely cases, yet effective practices remain variably applied and lacking in sensitivity and specificity. Here we report an interpretable deep learning strategy that delineates unique Alzheimer's disease signatures from multimodal inputs of MRI, age, gender, and Mini-Mental State Examination score. Our framework linked a fully convolutional network, which constructs high resolution maps of disease probability from local brain structure to a multilayer perceptron and generates precise, intuitive visualization of individual Alzheimer's disease risk en route to accurate diagnosis. The model was trained using clinically diagnosed Alzheimer's disease and cognitively normal subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 417) and validated on three independent cohorts: the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) (n = 382), the Framingham Heart Study (n = 102), and the National Alzheimer's Coordinating Center (NACC) (n = 582). Performance of the model that used the multimodal inputs was consistent across datasets, with mean area under curve values of 0.996, 0.974, 0.876 and 0.954 for the ADNI study, AIBL, Framingham Heart Study and NACC datasets, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n = 11), and high-risk cerebral regions predicted by the model closely tracked post-mortem histopathological findings. This framework provides a clinically adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for Alzheimer's disease diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.

COVID-19 in patients with myasthenia gravis.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic, but little is known about its potential impact on patients with myasthenia gravis (MG). METHODS: We studied the clinical course of COVID-19 in five hospitalized patients with autoimmune MG (four with acetylcholine receptor antibodies, one with muscle-specific tyrosine kinase antibodies) between April 1, 2020-April 30-2020. RESULTS: Two patients required intubation for hypoxemic respiratory failure, whereas one required significant supplemental oxygen. One patient with previously stable MG had myasthenic exacerbation. One patient treated with tocilizumab for COVID-19 was successfully extubated. Two patients were treated for MG with intravenous immunoglobulin without thromboembolic complications. DISCUSSION: Our findings suggest that the clinical course and outcomes in patients with MG and COVID-19 are highly variable. Further large studies are needed to define best practices and determinants of outcomes in this unique population.

A Clinician's Approach to Peripheral Neuropathy.

Peripheral neuropathies are a group of disorders that affect the peripheral nervous system, for which hundreds of etiologies have been identified. This article presents a stepwise approach to the evaluation and workup of peripheral neuropathy, which starts with a detailed history of symptoms, family and occupational history, and a neurological as well as general physical exam. Pattern recognition of various neuropathies can help to build a differential diagnosis based on the presentation. Such patterns include acute versus chronic, primary demyelinating versus axonal, hereditary versus acquired, asymmetric versus symmetric, presence of facial palsies, sensory or motor predominant, and presence of prominent autonomic symptoms. Early categorization of the type of neuropathy can help focus the workup for peripheral neuropathy. Nerve conduction studies and electromyography (NCS/EMG) is the primary diagnostic tool in the evaluation of patients with large-fiber polyneuropathy. One of the most important roles of NCS/EMG is to help categorize polyneuropathy as primary axonal versus primary demyelinating. The finding of a primary demyelinating polyneuropathy narrows the differential diagnosis of polyneuropathy dramatically and increases the chances of finding a treatable etiology. Laboratory workup includes serum studies and potentially cerebrospinal fluid, genetic studies, immunological markers, and fat pad biopsy for select patients. Skin biopsy may be used to assess intraepidermal nerve fiber density if small-fiber neuropathy is suspected, and nerve biopsy may be useful in select cases. In recent years, magnetic resonance imaging and neuromuscular ultrasound have also shown promise in the evaluation of peripheral neuropathy. Identification of the etiology of neuropathy is crucial and often time-sensitive, as an increasing number of causes are now reversible or treatable.

Neuropathy Associated with Systemic Amyloidosis.

Peripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations in the transthyretin (TTR) gene, which can lead to neuropathic hereditary transthyretin amyloidosis (hATTR; previously referred to as transthyretin familial amyloid polyneuropathy), whereas acquired immunoglobulin light chain (AL) amyloidosis is the most common acquired form. Patients typically present with a sensorimotor polyneuropathy, focal neuropathy such as carpal tunnel syndrome, or autonomic neuropathy. When neuropathy is the sole or dominant presenting symptom, the diagnosis is commonly delayed. With the advent of new drug therapies for AL amyloidosis and hATTR amyloidosis, including proteasome inhibitors, TTR silencers, and TTR protein stabilizers, the neurologist is uniquely positioned to diagnose neurologic manifestations of systemic amyloidosis, leading to earlier disease identification and treatment. This article reviews the epidemiology, clinical presentations, pathophysiology, diagnostic workup, and treatment of neuropathy in the setting of amyloidosis.

A Mixed-Methods Pilot Study of Mindfulness-Based Stress Reduction for HIV-Associated Chronic Pain.

Treatment guidelines for chronic pain recommend nonpharmacologic modalities as part of a comprehensive management plan. Chronic pain is common among people living with HIV/AIDS, but there is little data to guide the choice of nonpharmacologic therapies in this complex population. We performed a mixed-methods feasibility study of Mindfulness-Based Stress Reduction (MBSR) versus health education control with 32 inner city, HIV-infected participants. Outcome measures included: the Brief Pain Inventory, Perceived Stress Scale, HIV Symptoms Index, autonomic function testing, and audiotaped focus groups. Post-intervention, participants reported modest improvements in pain measures and perceived stress, but no effect of group assignment was observed. At 3-month follow-up, 79% of MBSR participants were still practicing, and pain intensity was improved, whereas in the control group pain intensity had worsened. Qualitative analysis revealed a strong sense of community in both groups, but only MBSR was perceived as useful for relaxation and pain relief.

Pathways in the diagnosis and management of diabetic polyneuropathy.

Distal symmetric polyneuropathy (DSPN), the most common form of diabetic neuropathy, has a complex pathophysiology and can be a major source of physical and psychologic disability. The management of DSPN can be frustrating for both patient and physician. This article provides a general overview of typical patient pathways in DSPN, and highlights variations in diagnosis, management, and referral patterns among different providers. DSPN is managed in several settings by primary care physicians (PCPs), specialists, and nurse practitioners. The initial clinical management of the patient is often dependent on the presenting complaint, the referral pattern of the provider, level of comfort of the PCP in managing diabetic complications, and geographic access to specialists. The primary treatment of DSPN focuses mainly on glycemic control and adjustment of modifiable risk factors, but other causes of neuropathy should also be investigated. Several pharmacologic agents are recommended by treatment guidelines, and as DSPN typically exists with comorbid conditions, a multimodal therapeutic approach should be considered. Barriers to effective management include failure to recognize DSPN, and misdiagnosis. Patient education also remains important. Referral patterns vary widely according to geographic location, access to services, provider preferences, and comfort in managing complex aspects of the disease. The variability in patient pathways affects patient education, satisfaction, and outcomes. Standardized screening tools, a multidisciplinary team approach, and treatment algorithms for diabetic neuropathy should improve future care. To improve patient outcomes, DSPN needs to be diagnosed sooner and interventions made before significant nerve damage occurs.

Podcast-Based Medical Education and Content Alignment with National Education Bodies.

Introduction: Despite the rapid expansion of medical education podcasts in the past decade, there are few efforts to characterize the landscape of available content for specific medical specialties. We trialed a method of rigorous characterization for the field of neurology. Materials and Methods: Using a censoring date of July 25, 2022, we queried the top three podcast platforms for neurology education podcasts: Apple Podcasts, Spotify, and Google Podcasts. We characterized podcasts based on total number of episodes, episode release frequency, target audience, and affiliation type. We characterized individual episodes by length and primary content area as defined by the Accreditation Council for Graduate Medical Education (ACGME) and American Board of Psychiatry and Neurology (ABPN). We compared content availability with content recommendations from these education bodies. Results: We identified 30 podcasts sharing 1772 episodes and totaling 46,287 min. The ACGME subspecialties most frequently covered were vascular neurology (5082 total min, 11%), neuroimmunology (4,406, 10%), and neuromuscular diseases (3,771, 8%). Subjects that were underrepresented included palliative neurology (89 min, 0.2%), neuropathology (95 min, 0.2%), and bioethics (171 min, 0.4%). The coverage of ABPN examination topics varied substantially from the content distribution for the examination. Discussion: The current landscape of neurology education podcasts features heterogeneous coverage of topics and varies considerably from recommended distribution of content by national education bodies. As podcasts have tremendous potential in supplementing neurology education, characterizing available content may help various stakeholders in the neurology education pipeline optimize the use of this e-learning modality. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01971-0.

Incobotulinum Toxin-A in Professional Musicians with Focal Task-Specific Dystonia: A Double Blind, Placebo Controlled, Cross-Over Study.

Background: Musician's focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers. Methods: We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment. Findings: 19 men and 2 women with musicians' dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found. Interpretation: Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians' task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians' dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer's cramp, and spasmodic dysphonia.

Newborn infants learn during sleep.

Newborn infants must rapidly adjust their physiology and behavior to the specific demands of the novel postnatal environment. This adaptation depends, at least in part, on the infant's ability to learn from experiences. We report here that infants exhibit learning even while asleep. Bioelectrical activity from face and scalp electrodes was recorded from neonates during an eye movement conditioning procedure in which a tone was followed by a puff of air to the eye. Sleeping newborns rapidly learned the predictive relationship between the tone and the puff. Additionally, in the latter part of training, these infants exhibited a frontally maximum positive EEG slow wave possibly reflecting memory updating. As newborns spend most of their time sleeping, the ability to learn about external stimuli in the postnatal environment during nonawake states may be crucial for rapid adaptation and infant survival. Furthermore, because eyelid conditioning reflects functional cerebellar circuitry, this method potentially offers a unique approach for early identification of infants at risk for a range of developmental disorders including autism and dyslexia.

Clinical Reasoning: A 23-Year-Old Man With Progressive Asymmetric Weakness and Numbness.

We report a case of a 23-year-old man who presented with progressive asymmetric weakness and numbness in his distal extremities over 4 months, with initial symptoms starting days after a coronavirus 2019 (COVID-19) vaccine booster. Initial neurologic examination was notable for distal weakness of both upper and lower extremities that was more pronounced on the left, complete areflexia, and decreased distal sensation to pinprick and vibration without loss of proprioception. Nerve conduction studies demonstrated a generalized, non-length-dependent, sensorimotor, demyelinating polyneuropathy, with conduction block seen in multiple compound muscle action potentials. Sensory nerve action potentials were normal in absolute terms but had asymmetric amplitudes.Based on the patient's nerve conduction studies, he was diagnosed with a specific immune-mediated neuromuscular disorder. He was started on intravenous immunoglobulin, but within days of the first infusions experienced a rare and potentially life-threatening complication. He received appropriate treatment and was started on alternative immunotherapy, after which his symptoms improved.Our case exemplifies the features of a specific subtype of a more common immune-mediated neuromuscular diagnosis with unique elements of history, examination, and nerve conduction studies that required interpretation in the clinical context. We also discuss a rare side effect of a commonly used immunotherapy and its risk factors and comment on the likelihood that this diagnosis may be related to a preceding COVID-19 vaccine booster.

Hereditary gelsolin amyloidosis: a rare cause of cranial, peripheral and autonomic neuropathies linked to D187N and Y447H substitutions.

INTRODUCTION: Hereditary gelsolin (AGel) amyloidosis is a systemic disease that is characterised by neurologic, ophthalmologic, dermatologic, and other organ involvements. We describe the clinical features with a focus on neurological manifestations in a cohort of patients with AGel amyloidosis referred to the Amyloidosis Centre in the United States. METHODS: Fifteen patients with AGel amyloidosis were included in the study between 2005 and 2022 with the permission of the Institutional Review Board. Data were collected from the prospectively maintained clinical database, electronic medical records and telephone interviews. RESULTS: Neurologic manifestations were featured in 15 patients: cranial neuropathy in 93%, peripheral and autonomic neuropathy in 57% and bilateral carpal tunnel syndrome in 73% of cases. A novel p.Y474H gelsolin variant featured a unique clinical phenotype that differed from the one associated with the most common variant of AGel amyloidosis. DISCUSSION: We report high rates of cranial and peripheral neuropathy, carpal tunnel syndrome and autonomic dysfunction in patients with systemic AGel amyloidosis. The awareness of these features will enable earlier diagnosis and timely screening for end-organ dysfunction. The characterisation of pathophysiology will assist the development of therapeutic options in AGel amyloidosis.

Toward an electrocortical biomarker of cognition for newborn infants.

The event-related potential (ERP) effect of mismatch negativity (MMN) was the first electrophysiological probe to evaluate cognitive processing (change detection) in newborn infants. Initial studies of MMN predicted clinical utility for this measure in identification of infants at risk for developmental cognitive deficits. These predictions have not been realized. We hypothesized that in sleeping newborn infants, measures derived from wavelet assessment of power in the MMN paradigm would be more robust markers of the brain's response to stimulus change than the ERP-derived MMN. Consistent with this premise, we found increased power in response to unpredictable and infrequent tones compared to frequent tones. These increases were present at multiple locations on the scalp over a range of latencies and frequencies and occurred even in the absence of an ERP-derived MMN. There were two predominant effects. First, theta band power was elevated at middle and late latencies (200 to 600 ms), suggesting that neocortical theta rhythms that subserve working memory in adults are present at birth. Second, late latency (500 ms) increased power to the unpredictable and infrequent tones was observed in the beta and gamma bands, suggesting that oscillations involved in adult cognition are also present in the neonate. These findings support the expectation that frequency dependent measures, such as wavelet power, will improve the prospects for a clinically useful test of cortical function early in the postnatal period.

Neurological manifestations of hereditary transthyretin amyloidosis: a focus on diagnostic delays.

BACKGROUND: The recent availability of disease-modifying therapies for hereditary transthyretin amyloid (ATTRv) amyloidosis warrants urgency for earlier diagnosis and timely identification of active disease state among genetic carriers. METHODS: We reviewed clinical neurological data of all patients with ATTRv amyloidosis with initial visits at our amyloidosis centre between January 2016 and December 2018. We abstracted the signs and symptoms of neurological manifestations, as well as rates and patterns of diagnostic testing. RESULTS: Of 92 patients with 19 different transthyretin (TTR) mutations, 66 and 36% had symptoms attributed to large-fibre and small-fibre neuropathy, respectively, compared to 75 and 66% with corresponding examination findings. Thirty-six patients with V122I ATTR mutation had asymptomatic polyneuropathy identified on neurological examination, eight without concurrent cardiac disease. Seventy-three percent of patients had symptoms of carpal tunnel syndrome (CTS), while 26% had dysautonomia. The average delays between the onset of symptoms of large fibre neuropathy (LFN) or CTS to ATTRv amyloidosis diagnosis were 2.9 and 6.7 years, respectively. DISCUSSION: Our study found higher rates of polyneuropathy by examination than patient-reported symptoms, especially among those with V122I TTR amyloidosis, signalling asymptomatic polyneuropathy. Our findings suggest the need for routine neurological examinations and other testing for genetic carriers to achieve earlier identification of active disease state.