Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records.

BACKGROUND: New treatments for transthyretin amyloidosis improve survival, but diagnosis remains challenging. Pathogenic or likely pathogenic (P/LP) variants in the transthyretin (TTR) gene are one cause of transthyretin amyloidosis, and genomic screening has been proposed to identify at-risk individuals. However, data on disease features and penetrance are lacking to inform the utility of such population-based genomic screening for TTR. OBJECTIVES: This study characterized the prevalence of P/LP variants in TTR identified through exome sequencing and the burden of associated disease from electronic health records for individuals with these variants from a large (N = 134,753), primarily European-ancestry cohort. METHODS: We compared frequencies of common disease features and cardiac imaging findings between individuals with and without P/LP TTR variants. RESULTS: We identified 157 of 134,753 (0.12%) individuals with P/LP TTR variants (43% male, median age 52 [Q1-Q3: 37-61] years). Seven P/LP variants accounted for all observations, the majority being V122I (p.V142I; 113, 0.08%). Approximately 60% (n = 91) of individuals with P/LP TTR variants (all V122I) had African ancestry. Diagnoses of amyloidosis were limited (2 of 157 patients), although related heart disease diagnoses, including cardiomyopathy and heart failure, were significantly increased in individuals with P/LP TTR variants who were aged >60 years. Fourteen percent (7 of 49) of individuals aged ≥60 or older with a P/LP TTR variant had heart disease and ventricular septal thickness >1.2 cm, only one of whom was diagnosed with amyloidosis. CONCLUSIONS: Individuals with P/LP TTR variants identified by genomic screening have increased odds of heart disease after age 60 years, although amyloidosis is likely underdiagnosed without knowledge of the genetic variant.

West Nile virus neuroinvasive disease associated with rituximab therapy.

West Nile virus neuroinvasive disease (WNVND) manifests with meningitis, encephalitis, and/or acute flaccid paralysis. It represents less than 1% of the clinical syndromes associated with West Nile virus (WNV) infection in immunocompetent patients. Immunosuppressive therapy is associated with increased risk of WNVND and worse prognosis. We present a patient with WNVND during therapy with rituximab, and a review of the literature for previous similar cases with the goal to describe the clinical spectrum of WNVND in patients treated specifically with rituximab. Our review indicates that the most common initial complaints are fever and altered mental status, brain magnetic resonance imaging often shows bilateral thalamic hyperintensities, and cerebrospinal analysis consistently reveals mild lymphocytic pleocytosis with elevated protein, positive WNV polymerase chain reaction, and negative WNV antibodies. Treatment is usually supportive care, with intravenous immunoglobulins (IVIG) plus corticosteroids and WNV-specific IVIG also used. The disease is usually fatal despite intervention. Our patient's presentation was very similar to prior reports, however demonstrated spontaneous improvement with supportive management only. WNVND is a rare and serious infection with poor prognosis when associated with rituximab therapy. Diagnosis is complicated by absent or delayed development of antibodies. The presence of bilateral thalamic involvement is a diagnostic clue for WNVND. There is insufficient evidence to recommend the use of corticosteroids or IVIG.

A Case of Hypertrophic Pachymeningitis Associated with Immunoglobulin-G4 and c-ANCA.

Hypertrophic pachymeningitis (HP) is characterized by inflammation of the dura mater. It has been described in the setting of numerous systemic inflammatory diseases including immunoglobulin G4 (IgG4)-related disease as well as granulomatosis with polyangiitis (GPA). In this case report, we describe a 48-year-old man presenting with headache who was found to have HP and had systemic features of both GPA and IgG4-related disease as well as seropositivity for both cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and IgG4. He was treated with prednisone and rituximab with improvement in his symptoms. Co-occurrence of IgG4 and ANCA against myeloperoxidase has been reported in other cases of HP. The overlap between IgG4 and ANCA has also been described in other systemic manifestations of the diseases. These reports suggest a clinical overlap between ANCA and IgG4-related disease, and the case presented herein suggests an overlap between GPA and IgG4-related disease.

Proximal Limb Weakness in a Patient with Celiac Disease: Copper Deficiency, Gluten Sensitivity, or Both as the Underlying Cause?

Celiac disease has been associated with several neurologic disorders which may result from micronutrient deficiencies, coexisting autoimmune conditions, or gluten sensitivity. Copper deficiency can produce multiple neurologic manifestations. Myeloneuropathy is the most common neurologic syndrome and it is often irreversible, despite copper replacement. We report the case of a 55-year-old man who presented with progressive proximal limb weakness and weight loss in the setting of untreated celiac disease without gastrointestinal symptoms. He had anemia, neutropenia, and severe hypocupremia. The pattern of weakness raised the suspicion that there was an underlying myopathy, although this was not confirmed by electrodiagnostic studies. Weakness and hematologic abnormalities resolved completely within 1 month of total parenteral nutrition with copper supplementation and a gluten-free diet. Myopathy can rarely occur in patients with celiac disease, but the mechanism is unclear. Pure proximal limb weakness has not been previously reported in copper deficiency. We propose that this may represent a novel manifestation of hypocupremia and recommend considering copper deficiency and gluten sensitivity in patients presenting with proximal limb weakness.

The neurology of solid organ transplantation.

Transplantation is the rescue treatment for end-stage organ failure with more than 110,000 solid organs transplantations performed worldwide annually. Recent advances in transplantation procedures and posttransplantation management have improved long-term survival and quality of life of transplant recipients, shifting the focus from acute perioperative critical care needs toward long-term chronic medical problems. Neurologic complications affect up to 30-60 % of solid organ transplant recipients. Common etiologies include opportunistic infections and toxicities of antirejection medications, and wide spectrum of toxic and metabolic disturbances. Most complications are common to all allograft types, but some are relatively specific for individual allograft types (e.g., central pontine myelinolysis in liver transplant recipients). Close collaboration between neurologists and other transplant team members is essential for effective management. Early recognition of complications and accurate diagnosis leading to timely treatment is essential to reduce the morbidity and improve the overall transplant outcome.