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Peripheral neuropathies account for the most frequent disorders seen by neurologists, and causes are manifold. The traditional diagnostic gold-standard consists of clinical neurologic examinations supplemented by nerve conduction studies. Due to well-known limitations of standard diagnostics and atypical clinical presentations, establishing the correct diagnosis can be challenging but is critical for appropriate therapies. Magnetic resonance neurography (MRN) is a relatively novel technique that was developed for the high-resolution imaging of the peripheral nervous system. In focal neuropathies, whether traumatic or due to nerve entrapment, MRN has improved the diagnostic accuracy by directly visualizing underlying nerve lesions and providing information on the exact lesion localization, extension, and spatial distribution, thereby assisting surgical planning. Notably, the differentiation between distally located, complete cross-sectional nerve lesions, and more proximally located lesions involving only certain fascicles within a nerve can hold difficulties that MRN can overcome, when basic technical requirements to achieve sufficient spatial resolution are implemented. Typical MRN-specific pitfalls are essential to understand in order to prevent overdiagnosing neuropathies. Heavily T2-weighted sequences with fat saturation are the most established sequences for MRN. Newer techniques, such as T2-relaxometry, magnetization transfer contrast imaging, and diffusion tensor imaging, allow the quantification of nerve lesions and have become increasingly important, especially when evaluating diffuse, non-focal neuropathies. Innovative studies in hereditary, metabolic or inflammatory polyneuropathies, and motor neuron diseases have contributed to a better understanding of the underlying pathomechanism. New imaging biomarkers might be used for an earlier diagnosis and monitoring of structural nerve injury under causative treatments in the future. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01166-8.

Symptoms of peripheral nervous system (PNS) damage are common clinical manifestations of systemic amyloidosis. Peripheral amyloid neuropathy is characterized by a progressive course, leading to the disability of patients; however, the current possibilities of pathogenetic therapy make the early diagnosis of amyloid neuropathy particularly urgent.Objective: to evaluate the informative value of laser confocal microscopy (LCM) of the cornea in diagnosing small fiber neuropathy of peripheral nerves in patients with systemic amyloidosis.Patients and methods. The study included nine patients (three men and six women) with morphologically confirmed primary amyloidosis (ALamyloidosis) and 12 patients (three men and nine women) with hereditary transthyretin amyloidosis (TTR-amyloidosis) verified by genetic and morphological methods. At baseline, the mean age of patients with AL-amyloidosis was 60.6±10.7 years, with hereditary TTR-amyloidosis – 57.1±13.1 years. According to the history of the disease in AL-amyloidosis, the mean duration of clinical symptoms was 2.7±1.4 years, with TTR-amyloidosis – 5.5±3.6 years. 20 age- and sex-adjusted healthy volunteers were included in the control group. All patients underwent a clinical neurological examination with an assessment of the severity of neuropathy according to the Neuropathy Impairment Score (NIS); 21 patients with systemic amyloidosis and all volunteers of the control group underwent LCM of the corneal nerve fibers (CNF). The coefficients of anisotropy (КΔL) and orientation symmetry (Ksym) of the CNF were calculated to assess the severity of damage to the corneal nerves.Results and discussion. Clinical neurological examination in patients with AL-amyloidosis revealed polyneuropathic syndrome (45%), tunnel syndrome (22%), their combination (22%), and autonomic dysfunction in the form of orthostatic hypotension and impaired motility of the gastrointestinal tract (GI tract; 56%). Symptoms in patients with TTR-amyloidosis were characterized by a combination of tunnel neuropathy and sensory-motor polyneuropathy (50%), distal symmetric polyneuropathy (42%). Frequent symptoms of PNS damage in systemic amyloidosis include autonomic neuropathy (56% – in AL-amyloidosis, 92% – in TTR-amyloidosis) presenting with orthostatic hypotension, impaired gastrointestinal motility, hypohidrosis, and dysuria. The mean NIS score, which characterizes the severity of somatic neuropathy, was significantly higher in patients with TTR-amyloidosis than AL-amyloidosis (pConclusion. Clinical polymorphism of peripheral somatic and autonomic nervous systems lesions is typical for patients with systemic amyloidosis. LCM of the cornea is informative in the diagnosis of small fibers neuropathy of peripheral nerves in systemic amyloidosis; however, it cannot establish the nosology of neuropathy.

Background Carpal tunnel syndrome is the most common compression syndrome of the peripheral nerve. Transthyretin amyloidosis and dialysis-related β2-microglobulin amyloidosis are known causes of carpal tunnel syndrome. Case Report A Japanese woman showed carpal tunnel syndrome 16 years after a domino liver transplantation (DLT) from the donor with hereditary transthyretin amyloidosis. DLT indication was congenital extrahepatic portosystemic shunt, and the patient had been put on maintenance hemodialysis because of chronic kidney disease 6 years before DLT. Moreover, the amyloid precursor protein of the patient was histologically confirmed not to be β2-microglobulin, but transthyretin. Conclusions The existence of amyloid was speculated when the patient who underwent DLT from hereditary transthyretin amyloidosis showed carpal tunnel syndrome. Additionally, elucidating the amyloid precursor protein when the patient has another cause of amyloidosis is necessary.

Background Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). Methods The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. Results Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. Conclusions 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

AA amyloidosis is characterized by amyloid deposition in systemic organs, but amyloid deposition in the central nervous system (CNS) or peripheral nervous system (PNS) is rare. In this study, AA amyloidosis was observed in 31 of 48 flamingos that died at a Japanese zoo. Almost all cases developed AA amyloidosis secondary to inflammatory diseases such as enteritis. Affected flamingos had AA amyloid deposition around blood vessels in periventricular white matter of the brain and in peripheral nerves. In addition, cerebral Aβ amyloidosis was observed in one of the 31 cases with AA amyloidosis. In conclusion, flamingos in the zoo commonly developed systemic amyloidosis with frequent amyloid deposition in the CNS and PNS, which seems to be a unique distribution in this avian species. Comparative pathological analyses in flamingos may help elucidate the pathogenesis of amyloid neuropathy.

Transthyretin (TTR) amyloid cardiomyopathy is a life-threatening condition in which amyloid fibrils accumulate in the heart, eventually leading to cardiac symptomatology and death. To date, treatment of this condition has been directed at symptom relief due to a lack of effective treatment options which target the cause of the disease. The discovery that amyloid deposition was a result of dissociation of the TTR protein structure allowed for the development of tafamidis, which acts by stabilizing the TTR tetramer. Due to the rare nature of the disease, there is limited clinical trial data with tafamidis, with the largest clinical trial enrolling only 441 patients. Nonetheless, that trial demonstrated tafamidis to reduce all-cause mortality as well as cardiovascular hospitalizations compared to placebo with a comparable adverse effect profile, although not all subgroups of patients received benefit. The United States Food and Drug Administration subsequently granted Fast Track review status to tafamidis, leading to its approval in May 2019. Important questions still remain, however, such as which patient groups will receive the most benefit with this drug, how the exceptionally high cost of the drug will be handled by third-party payers, and how the therapeutic role of tafamidis will evolve as competing or perhaps complementary medications complete their ongoing clinical trials and move into the marketplace.

Hereditary transthyretin amyloidosis, once a rare progressive neuropathy and/or cardiomyopathy, is now recognized with increasing worldwide frequency, various phenotypes, and over 130 gene mutations identified to date. This inherited disorder develops as a result of mutated transthyretin amyloid aggregation and systematic deposition throughout the body. With increasing knowledge about the pathophysiology of this disease, new disease-modifying therapies are being developed. In addition to slowing progression, these new agents were found to improve quality of life and reduce the severity of neuropathic symptoms. Two new gene-modifying therapies recently received Food and Drug Administration approval following the positive results from phase III trials. These include an antisense oligonucleotide, inotersen, and small interfering RNA, patisiran, which were reported to reduce the production of transthyretin and had promising safety profiles. Additional novel therapies are being explored with hopes to prolong survival. Therefore, early diagnosis of this treatable disorder has become increasingly important in clinical practice.

The diagnosis of polyneuropathy (PNP) is based on the anamnesis and description of complaints of the patient and clinical findings. The type of distribution as well as known diseases and drug toxic factors can provide indications. Electromyography and electroneurography can be used to differentiate between axonal and demyelinating PNP. The laboratory examinations are initially directed towards frequent and treatable causes. These are then expanded depending on the suspected diagnosis. Analysis of cerebrospinal fluid (CSF) is facultative and should be carried out when there is a suspicion of a certain form of PNP with CSF findings indicative of the diagnosis. Nerve biopsy is indicated when the etiology of a severe or progressive PNP cannot be clarified by less invasive means and can have consequences for the treatment. A genetic investigation can be meaningful with a positive family anamnesis or with typical signs of hereditary PNP. Depending on the neuropathy and context, the diagnostic approach is structured differently. The special diagnostics for small fiber neuropathy and amyloid neuropathy as well as for diabetes and alcohol abuse are dealt with in detail in this article. Numerous cases of polyneuropathy remain unexplained and regularly have a favourable prognosis.

Амилоидоз — группа заболеваний, характеризующихся внеклеточным отложением специфического гликопротеина (амилоида), что приводит к увеличению их размеров, повреждению/гибели клеток, нарушению их функции. Клиническая картина разнообразна. Амилоидоз редко встречается и сложно диагностируется. В данной статье мы представляем некоторые клинические случаи больных с различными видами амилоидоза., Amyloidosis is a group of diseases characterized by the extracellular deposition of a specific glycoprotein (amyloid) that leads to an increase in their size, damage/death and dysfunction of cells and tissues. The clinical picture is varied. Amyloidosis is a rare disease and it is very difficult for the diagnosis. In this article, we are presenting some clinical cases of patients with various types of amyloidosis.

Background In Argentina, there is limited data of prevalence of variant transthyretin amyloidosis (ATTRv) and phenotype‐genotype correlation. The laboratory of Hospital Italiano de Buenos Aires (HIBA) is a reference center for transthyretin (TTR) gene sequencing. The Institutional Amyloidosis Registry (RIA) enable us to characterize people with ATTRv. Our aim was to describe the prevalence of TTR mutations at a reference center in Argentina and the phenotypic presentations of patients with ATTRv included in an institutional registry. Methods Retrospective cohort study of consecutive patients with genetic variants in the TTR gene identified from 2012 to 2019 in the laboratory. We collected all phenotypic characteristics of patients who were clinically evaluated by HIBA doctors. Results Five hundred seventy‐six patients tested, 141 positive: p.Val50Met 107, p.Thr80Ala 16, p.Ala117Ser 9, p.Phe84Leu 2, p.Ile127Val 2, p.Tyr134Cys 2, p.Ala56Pro 2, p.Val142Ile 1. Only 20 patients were clinically evaluated. The mean age at diagnosis was 54 years; 70% had family history with a pedigree median of 4. Mutations were p.Thr80Ala 9, p.Val50Met 6, p.Ala56Pro 2, p.Val142Ile 1, p.Phe84Leu 1, and p.Tyr134Cys 1. Eleven patients presented polyneuropathy, 11 had gastrointestinal compromise, six patients had autonomic compromise, six presented cardiac symptoms and four patients presented ocular involvement. Conclusion We present the first prevalence report of TTR mutations in a reference center of amyloidosis in Argentina. The most frequent genetic variant was p.Val50Met. Our data show considerable phenotypic heterogeneity in the patients with ATTRv., We present the first prevalence report of TTR mutations in a reference center of amyloidosis in Argentina. The most frequent genetic variant was p.Val50Met. Considerable phenotypic heterogeneity in patients with ATTRv.

Background Hereditary transthyretin-mediated amyloidosis, also known as ATTRv amyloidosis (v for variant), is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively impairs multiple organs, leading to disability and death. The recent approval of disease-modifying therapies offers the hope of stabilization or eventual reversal of disease progression, and yet highlights a lack of disease-management guidance. A multidisciplinary panel of expert clinicians from France and the US came to consensus on monitoring the disease and identifying progression through a clinical opinion questionnaire, a roundtable meeting, and multiple rounds of feedback. Monitoring disease and progression A multidisciplinary team should monitor ATTRv amyloidosis disease course by assessing potential target organs at baseline and during follow-up for signs and symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, and other manifestations. Variability in penetrance, symptoms, and course of ATTRv amyloidosis requires that all patients, regardless of variant status, undergo regular and standardized assessment in all these categories. Progression in ATTRv amyloidosis may be indicated by: worsening of several existing quantifiable symptoms or signs; the appearance of a new symptom; or the worsening of a single symptom that results in a meaningful functional impairment. Conclusions We suggest that a multisystem approach to monitoring the signs and symptoms of ATTRv amyloidosis best captures the course of the disease. We hope this work will help form the basis of further, consensus-based guidance for the treatment of ATTRv amyloidosis.

ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 Å cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils., Systemic amyloidosis of the ATTR is one of the most abundant forms of systemic amyloidosis and caused by misfolding of the circulating blood protein transthyretin (TTR). Here the authors present the cryo-EM structure of patient-derived Val30Met ATTR amyloid fibrils which reveals that the protofilament consists of an N-terminal and a C-terminal TTR fragment and discuss implications for the mechanism of misfolding.

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis with polyneuropathy (also known as familial amyloid polyneuropathy) is a condition with adult onset caused by mutation of transthyretin (TTR) and characterized by extracellular deposition of amyloid and destruction of the somatic and autonomic PNS, leading to loss of autonomy and death. This disease represents a model of the scientific and medical progress of the past 30 years. ATTRv amyloidosis is a worldwide disease with broad genetic and phenotypic heterogeneity that presents a diagnostic challenge for neurologists. The pathophysiology of the neuropathy is increasingly understood and includes instability and proteolysis of mutant TTR leading to deposition of amyloid with variable lengths of fibrils, microangiopathy and involvement of Schwann cells. Wild-type TTR is amyloidogenic in older individuals. The main symptoms are neuropathic, but the disease is systemic; neurologists should be aware of cardiac, eye and kidney involvement that justify a multidisciplinary approach to management. Infiltrative cardiomyopathy is usually latent but present in half of patients. Disease-modifying therapeutics that have been developed include liver transplantation and TTR stabilizers, both of which can slow progression of the disease and increase survival in the early stages. Most recently, gene-silencing drugs have been used to control disease in the more advanced stages and produce some degree of improvement.

Here we describe a patient with genetically confirmed ATTR, a family history of the disease and histological confirmation following carpal tunnel release surgery but no other manifestations. The first major neurological or systemic manifestation was cauda equina syndrome with ATTR deposits contributing to lumbar spinal stenosis. Recent gene therapy trials showed improvement in the neuropathy in TTR amyloidosis. This case highlights the need for awareness of the heterogeneous neurological phenotype seen in ATTR to aid earlier diagnosis especially now that disease modifying therapies are available.

Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver transplantation and small molecule stabilizers were not effective in stopping disease progression. Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.

Transthyretin amyloidosis patients develop length-dependent peripheral neuropathy, autonomic dysfunction, and restrictive cardiomyopathy associated with deposition of amyloid fibrils in these tissues. Despite advances in management over the past decade, this disorder causes profound debilitation and ultimately proves fatal. In this report, we describe a man with late-onset cardiac amyloidosis due to a transthyretin Thr60Ala mutation who was treated with an investigational RNAi therapeutic, revusiran, which targets hepatic transthyretin production. Sixteen months into treatment, he developed bilateral lower-extremity weakness and numbness, worsening balance, difficulty manipulating objects with his hands, and finger numbness. Nerve conduction studies were consistent with multifocal demyelinating neuropathy. Intravenous immunoglobulin therapy improved sensation in his hands and feet, and improved hand dexterity. A sural nerve biopsy demonstrated demyelination with substantial axonal loss in the absence of histologically detectable endoneurial amyloid deposition. This case expands the clinicopathologic spectrum of transthyretin amyloidosis and may represent complex disease and treatment effects.

Objective Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age at onset (AO) ranges from 19 to 82 years, and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of 10 genes had a possible modifier effect in AO in Portuguese TTR-FAP Val30Met families. Methods We analyzed 329 Portuguese patients from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK) was assessed by single and multiplex polymerase chain reaction, using fluorescently labeled primers, followed by capillary electrophoresis. We used a family-centered approach, and generalized estimating equations were used to account for AO correlation between family members. Results For ATXN2, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR-FAP Val30Met, decreasing mean AO by 6 years (95% confidence interval = -8.81 to -2.19, p = 0.001). No association was found for the remaining repeat loci. Interpretation Length of normal repeats at ATXN2 may modify AO in TTR-FAP Val30Met and may function as a risk factor. This can be due to the role of ATXN2 in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow-up of presymptomatic carriers. ANN NEUROL 2019;85:251-258.

Neuropathic pain has multiple etiologies, but a major feature is small fiber dysfunction or damage. Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that can image small nerve fibers in the cornea and has been utilized to show small nerve fiber loss in patients with diabetic and other neuropathies. CCM has comparable diagnostic utility to intraepidermal nerve fiber density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fiber loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease and dementia. We conclude that corneal confocal microscopy has good diagnostic and prognostic capability and fulfills the FDA criteria as a surrogate end point for clinical trials in peripheral and central neurodegenerative diseases.

Background and aims: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. Methods: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007–2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. Results: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age

SUMMARY OBJECTIVE: To review the literature and to report a clinical case with initial suspicion of pure neural leprosy and final diagnosis of amyloid neuropathy. METHODS: The study was conducted in two stages. In stage one, a systematic literature review was carried out, with searches performed in the PubMed, Medline, and Lilacs databases, as well as in the leprosy sectoral library of the Virtual Health Library, using the following descriptors: neuritic leprosy, pure neural leprosy, primary neural leprosy, pure neuritic leprosy, amyloid polyneuropathy, amyloid neuropathies, and amyloid polyneuropathy. The search was carried out on May 28, 2020. Clinical trials, cohort studies, cross-sectional studies, clinical cases, and case studies published in Portuguese, English or Spanish between 2010 and 2020 were included. Stage two reports a case with initial suspicion of pure neural leprosy. Laboratory tests, electroneuromyography, ultrasound, and biopsy of the sural nerve were requested. RESULTS: Twenty-three scientific texts were included. No publications were found that contained both topics together. The challenging diagnosis of pure neural leprosy and the possibility of using auxiliary resources in diagnosis were the most emphasized themes in the studies. In the clinical case, the patient's electroneuromyography showed sensitive and motor polyneuropathy of the lower limbs, which was predominantly sensory and axonal, symmetrical, of moderate intensity, and the mixed type (axonal-demyelinating). Ultrasonography of the sural nerve revealed changes in the contour of the deep fibular nerves; biopsy of the sural nerve showed an accumulation of amorphous eosinophilic material in the nerve path, and Congo red stain showed apple-green birefringence of the deposit under polarized light. The final diagnosis was amyloid neuropathy. CONCLUSIONS: The final clinical diagnosis was amyloid neuropathy. The diagnosis of pure neural leprosy in endemic areas in Brasil is still a challenge for the health system.

Imagine that you had several family members with transthyretin amyloidosis. In their sixth decade of life, numbness developed, initially in their hands and feet, that progressed proximally over a p...

Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so-called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long-standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine. Herein, we review the clinical manifestations of neuromuscular amyloidosis and provide a diagnostic approach to this disorder.