Comprehensive approach to cardiac amyloidosis care: considerations in starting an amyloidosis program.

Amyloidosis is a multisystem disease which continues to present in later stages due to delayed diagnosis. Once the disease is identified, the coordination of ongoing care and treatment becomes complex and often involves multiple specialists. As knowledge of the disease grows, healthcare providers within institutions have organized to create comprehensive amyloidosis programs to better serve patients in the region. In this review, we present considerations in starting a cardiac amyloidosis program from two institutions that have recently started such programs. Identification of multidisciplinary stakeholders, development of overarching program goals, creation of institutional buy-in, and emphasis on program growth and development are tenets of a successful program. The creation and growth of an amyloidosis program has the potential to raise awareness for the disease and benefit patients and institutions alike.

A process for developing standards to promote quality in general practice.

BACKGROUND: Since 1991, the Royal Australian College of General Practitioners' (RACGP) Standards for General Practices (the Standards) have provided a framework for quality care, risk management and best practice in the operation of Australian general practices. The Standards are also linked to incentives for general practice remuneration. These Standards were revised in 2017. OBJECTIVE: The objective of this study is to describe the process undertaken to develop the fifth edition Standards published in 2017 to inform future standards development both nationally and internationally. METHOD: A modified Delphi process was deployed to develop the fifth edition Standards. Development was directed by the RACGP and led by an expert panel of GPs and representatives of stakeholder groups who were assisted and facilitated by a team from RACGP. Each draft was released for stakeholder feedback and tested twice before the final version was submitted for approval by the RACGP board. RESULTS: Four rounds of consultation and two rounds of piloting were carried out over 32 months. The Standards were redrafted after each round. One hundred and fifty-two individuals and 225 stakeholder groups participated in the development of the Standards. Twenty-three new indicators were recommended and grouped into three sections in a new modular structure that was different from the previous edition. CONCLUSION: The Standards represent the consensus view of national stakeholders on the indicators of quality and safety in Australian general practice and primary care.

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial.

INTRODUCTION: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. METHODS: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. RESULTS: The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. CONCLUSIONS: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Defects of mutant DNMT1 are linked to a spectrum of neurological disorders.

We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

Hirayama Disease: A 15-Year-Old Male With Progressive Distal Right Upper Extremity Weakness.

INTRODUCTION: Hirayama disease is a rare neuromuscular disorder characterized by abnormal forward displacement of the cervical spinal cord, resulting in focal ischemic changes of anterior horn cells. CASE REPORT: A 15-year-old male presented with 6 months of progressive right upper extremity weakness. Electromyography/nerve conduction study indicated a chronic neurogenic process involving the C8-T1 myotome. Cervical spine magnetic resonance imaging in the neutral position demonstrated minor disk bulges without significant spinal canal narrowing. With flexion, there was a forward displacement of the dorsal dural sac and marked effacement of the subarachnoid spaces from vertebral levels C5 through C7. In addition, prominent flow voids were now seen in the dorsal epidural space consistent with engorged venous structures. CONCLUSION: The diagnosis of Hirayama disease requires a high index of suspicion, and imaging should include a series with the neck in a flexed position, as imaging in the neutral position is often unrevealing and the disorder can otherwise easily be missed.

Iatrogenic seizures during intracranial EEG monitoring.

Cerebral edema with declining neurologic status is a known complication of intracranial electroencephalography (EEG) monitoring. The frequency and consequences of iatrogenic edema that is not clinically evident are presently poorly defined. We investigated the potential for intracranial electrodes to cause subclinical cerebral edema, and for such edema to cause iatrogenic seizures. In a retrospective review of 33 adults who had head magnetic resonance imaging (MRI) while undergoing epilepsy surgery evaluation with intracranial EEG, 28% (6 of 21) depth electrode implantations had subclinical vasogenic edema. Of these, 50% (3 of 6) had nonhabitual electrographic seizures that appear to result from iatrogenic edema. No long-term adverse sequelae were noted, however, if unrecognized, iatrogenic seizures could lead to unnecessary exclusion from definitive surgical intervention for refractory epilepsy.

COVID-19 Dysautonomia.

Objective: To report a case series of dysautonomia associated with COVID-19 infection. Methods: This is a retrospective review of patients evaluated in the autonomic clinic at our institution with suspected signs and symptoms of dysautonomia who underwent formal evaluation, including autonomic testing. Results: Six patients were identified with signs and symptoms suggestive of dysautonomia who underwent autonomic testing. All patients had symptoms typical of COVID-19 infection, though none were hospitalized for these or other symptoms. All patients reported symptoms of postural lightheadedness and near-syncope, fatigue, and activity intolerance. Five patients reported the onset of autonomic symptoms concomitant with other COVID-19 symptoms, with the other patient reporting symptom onset 6 weeks following initial COVID-19 symptoms. Autonomic testing demonstrated an excessive postural tachycardia in 4 patients, a hypertensive response with head-up tilt in 3 patients, orthostatic hypotension in 1 patient, and sudomotor impairment in 1 of the patients with excessive postural tachycardia. Conclusions: We present clinical features and results of autonomic testing in 6 patients with a history COVID-19 infection. While all patients reported typical features of orthostatic intolerance, fatigue, and activity intolerance, the results of autonomic testing were heterogenous, with orthostatic hypotension in 1 patient, excessive postural tachycardia typical of postural tachycardia syndrome in 4 patients, and postural hypertension in 3 patients.

Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of central nervous system sarcoidosis.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disease that may involve the central nervous system (CNS) in many ways, leading to diagnostic difficulties. An accurate diagnostic laboratory test would enhance the evaluation and management of these patients. OBJECTIVE: To determine the diagnostic accuracy of cerebrospinal fluid angiotensin-converting enzyme (ACE) for CNS neurosarcoidosis. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neuroimmunology. RESULTS: Two primary articles were selected for review. Cerebrospinal fluid ACE assay is insensitive (24%-55%) but may be reasonably specific (94%-95%) for CNS neurosarcoidosis. However, existing data are derived from studies with significant methodological and reporting limitations. CONCLUSIONS: The diagnostic accuracy of cerebrospinal fluid ACE for CNS neurosarcoidosis is not clearly established and the test cannot replace tissue diagnosis. Despite its insensitivity, some clinicians might consider the specificity of cerebrospinal fluid ACE, based on existing data, high enough to warrant inclusion in the diagnostic evaluation of patients in whom CNS neurosarcoidosis is being considered. A well-designed prospective diagnostic study seems warranted.

The clinical utility of high resolution magnetic resonance imaging in the diagnosis of giant cell arteritis: a critically appraised topic.

BACKGROUND: Giant cell arteritis (GCA) is a relatively common form of systemic vasculitis, known for its predisposition to affect extracranial branches of the carotid artery and associated potential for causing visual loss and stroke. Neurologists need to be vigilant for this disorder, diagnose it early, and institute effective corticosteroid therapy. The differential diagnosis can be broad. Unfortunately, all clinical and laboratory features of GCA are limited by either low sensitivity or low specificity. Temporal artery biopsy remains the gold standard, but it has its own limitations. Noninvasive imaging techniques, like magnetic resonance imaging (MRI), may be capable of detecting the occurrence of GCA. OBJECTIVE: How useful is high resolution MRI as a diagnostic test in establishing the diagnosis of GCA? METHODS: We addressed the question through development of a structured critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarian, and clinical content experts in the field of neuroradiology, rheumatology, and vascular neurology. Participants started with a clinical scenario and a structured question, devised search strategies, located and compiled the best evidence, performed critical appraisals, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. RESULTS: A single study which assessed the diagnostic value of MRI against a reference standard in GCA was appraised. For the MRI, the estimated sensitivity was 81% (95% CI 67-95), specificity was 97% (91-100), positive likelihood ratio (LR) was 26.6 (95% CI 3.8-184.8), negative LR was 0.20 (95% CI 0.10-0.41). The study exhibited several methodological weaknesses which interfered with its validity. CONCLUSIONS: The specificity and positive LR of high resolution MRI are sufficiently high that a positive MRI combined with other clinical and laboratory data consistent with GCA may be useful in diagnosing GCA. Given the relatively low sensitivity of the test, a negative MRI would not be sufficient to rule out the diagnosis of GCA.

Spectrum of Autonomic Nervous System Impairment in Sjögren Syndrome.

OBJECTIVE: To describe the spectrum of autonomic dysfunction in a uniformly evaluated cohort of patients with Sjögren syndrome. METHODS: A series of 13 patients underwent a comprehensive evaluation for suspected autonomic impairment, including a neurological examination, autonomic testing, and laboratory studies. A diagnosis of Sjögren syndrome was established as the cause of autonomic dysfunction in all. Clinical features, findings on autonomic testing, and laboratory results are described. RESULTS: All patients in this series reported postural lightheadedness and syncope or near-syncope. Autonomic testing confirmed the presence of orthostatic hypotension on tilt-table testing in 5 patients and an excessive postural tachycardia and/or hypertensive response in 8 patients. Only 2 of the patients with orthostatic hypotension had a significant sensory neuropathy. Symptoms suggestive of gastrointestinal and genitourinary impairment were seen in nearly all patients, with abnormal motility testing (most frequently esophageal dysmotility) in 5 of 6 patients who underwent formal testing. Patients in this series treated with immune-modulating therapy experienced significant improvement. CONCLUSIONS: A diagnosis of Sjögren syndrome should be aggressively pursued in patients with signs and symptoms suggestive of autonomic nervous system impairment. Although the spectrum of adrenergic failure is variable, ranging from orthostatic hypotension to an excessive postural tachycardia, most patients do have symptoms of more generalized autonomic failure. Patients who were treated with immune-modulating therapy did improve.