Drug- and Toxin-Induced Opsoclonus - a Systematized Review, including a Case Report on Amantadine-Induced Opsoclonus in Multiple System Atrophy.

Background: Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus. Methods: Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies. Results: The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus. Conclusion: Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology.

Late cognitive and adaptive outcomes of patients with neuroblastoma-associated opsoclonus-myoclonus-ataxia-syndrome: A report from the Children's Oncology Group.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder of the nervous system presenting with abnormal eye and limb movements, altered gait, and increased irritability. Two to four percent of children diagnosed with neuroblastoma have neuroblastoma-associated OMAS (NA-OMAS). These children typically present with non-high-risk neuroblastoma that is cured with surgery, with or without chemotherapy. Despite excellent overall survival, patients with NA-OMAS can have significant persistent neurological and developmental issues. OBJECTIVE: This study aimed to describe long-term neurocognitive and adaptive functioning of patients with NA-OMAS treated with multimodal therapy, including intravenous immunoglobulin (IVIG) on Children's Oncology Group (COG) protocol ANBL00P3. METHODS: Of 53 children enrolled on ANBL00P3, 25 submitted evaluable neurocognitive data at diagnosis and at least one additional time point within 2 years and were included in the analyses. Adaptive development was assessed via the Vineland Adaptive Behavior Scale, and validated, age-appropriate measures of intellectual function were also administered. RESULTS: Twenty-one of the 25 patients in this cohort ultimately received IVIG. Descriptive spaghetti plots suggest that this cohort demonstrated stable long-term cognitive functioning and adaptive development over time. This cohort also demonstrated decreased OMAS scores over time consistent with improved OMAS symptoms. CONCLUSIONS: While statistical significance is limited by small sample size and loss to follow-up over 10 years, findings suggest stable long-term cognitive and adaptive functioning over time in this treated cohort.

Characteristics of Opsoclonus-Myoclonus Syndrome in Patients of the Largest Pediatric Hospital in Latin America.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare neuroinflammatory disorder characterized by ataxia, opsoclonus, and myoclonus. Clinical diagnosis of OMS has been challenging; therefore, we sought to determine the clinical and treatment profiles of patients with OMS at the largest pediatric hospital in Latin America. METHODS: We analyzed the data of patients diagnosed with OMS between 2010 and 2020 at Pequeno Principe Hospital (Brazil) to determine the corresponding clinical profile more accurately. RESULTS: Of the approximately 50,000 visitors to our pediatric neurology department from 2010 to 2020, 10 patients with OMS were observed. Five nontumor cases included three parainfectious and two idiopathic cases. The median time from symptom onset to diagnosis was 34 days. All patients with diagnostic OMS criteria in the idiopathic, nontumor group underwent whole-exome sequencing, with potentially pathogenic mutations identified in two cases. Nine patients were treated with methylprednisolone pulse, followed by oral steroids; eight received one or more intravenous immunoglobulin treatments; and six received azathioprine and cyclophosphamide. Complete symptomatic recovery was observed in only one patient. CONCLUSIONS: OMS diagnosis remains challenging. Diagnostic suspicion is necessary to improve the management of these patients and allow early immunosuppressive treatment. Paraneoplastic etiology is the most prevalent. In idiopathic patients who do not respond to immunosuppressive treatment, tests, such as whole-exome sequencing, may reveal a differential diagnosis. Genetic alterations that increase the risk of tumors may be an important clue to the pathophysiology of OMS.

Retrospective analysis of COVID-19 patients with Guillain-Barre, Miller-Fisher, and opsoclonus-myoclonus-ataxia syndromes-a case series.

BACKGROUND: In accordance with the rising number of SARS-CoV­2 infections, reports of neurological complications have also increased. They include cerebrovascular diseases but also immunological diseases such as Guillain-Barre syndrome (GBS), Miller-Fisher syndrome (MFS), and opsoclonus-myoclonus-ataxia syndrome (OMAS). While GBS and MFS are typical postinfectious complications, OMAS has only recently been described in the context of COVID-19. GBS, MFS, and OMAS can occur as para- and postinfectious, with different underlying pathomechanisms depending on the time of neurological symptom onset. The study aimed to describe clinical features, time between infection and onset of neurological symptoms, and outcome for these diseases. METHODS: All COVID-19 patients treated in the neurological ward between January 2020 and December 2022 were screened for GBS, MFS, and OMAS. The clinical features of all patients, with a particular focus on the time of onset of neurological symptoms, were analyzed. RESULTS: This case series included 12 patients (7 GBS, 2 MFS, 3 OMAS). All GBS and one MFS patient received immunomodulatory treatment. Three patients (2 GBS, 1 OMAS) had a severe COVID-19 infection and received mechanical ventilation. In patients with OMAS, only one patient received treatment with intravenous immunoglobulin and cortisone. The remaining two patients, both with disease onset concurrent with SARS-COV­2 infection, recovered swiftly without treatment. In all subgroups, patients with concurrent onset of neurological symptoms and COVID-19 infection showed a trend toward shorter disease duration. CONCLUSION: All patient groups displayed a shorter disease duration if the onset of neurological symptoms occurred shortly after the COVID-19 diagnosis. In particular, both the OMAS patients with symptom onset concurrent with COVID-19 showed only abortive symptoms followed by a swift recovery. This observation would suggest different pathomechanisms for immune-mediated diseases depending on the time of onset after an infection.

Adult-onset idiopathic opsoclonus-myoclonus syndrome / Síndrome de opsoclonia-mioclonia idiopática de início adulto

ABSTRACT Purpose: Opsoclonus-myoclonus syndrome is extremely uncommon in adults with an autoimmune pathophysiology. Because of the rarity of the syndrome, international recognition of opsoclonus-myoclonus-ataxia syndrome needs to be improved urgently. Therefore, the goal of this study was to raise the awareness of the opsoclonus-myoclonus-ataxia syndrome and help doctors in better diagnosing and using immunotherapy. Methods: We present a case study of an adult-onset case of idiopathic opsoclonus-myoclonus syndrome characterized by spontaneous arrhythmic multidirectional conjugate eye movements, myoclonus, ataxia, sleep disorders, and intense fear. Additionally, we conduct a literature search and summarize the pathophysiology, clinical presentation, diagnosis, and treatment of opsoclonus-myoclonus-ataxia syndrome. Results: Immunotherapies successfully treated the patient's opsoclonus, myoclonus, and ataxia. Further, the article also includes an update summary of the opsoclonus-myoclonus-ataxia syndrome. Conclusion: The prevalence of residual sequela in adults with opsoclonus-myoclonus-ataxia syndrome is low. Early diagnosis and treatment may result in a better prognosis. Furthermore, combined immunotherapy is expected to reduce the incidence of refractory and reoccurring opsoclonus-myoclonus-ataxia syndrome.

RESUMO Objetivo: A síndrome de opsoclonia-mioclonia é extremamente rara em adultos e tem uma fisiopatologia autoimune. Devido à raridade dessa síndrome, o reconhecimento da síndrome de opsoclonia-mioclonia-ataxia precisa melhorar urgentemente em todo o mundo. Assim sendo, este estudo visou aumentar a conscientização sobre a síndrome de opsoclonia-mioclonia-ataxia e ajudar os médicos para um melhor diagnóstico e o uso correto da imunoterapia. Métodos: Este é o relato de um caso adulto de síndrome de opsoclonia-mioclonia idiopática com movimentos oculares conjugados, multidirecionais, arrítmicos e espontâneos, mioclonia, ataxia, distúrbios do sono e medo intenso. Além disso, foram pesquisadas as publicações recentes relevantes e resumiu-se a fisiopatologia, a apresentação clínica, o diagnóstico e o tratamento da síndrome de opsoclonia-mioclonia-ataxia. Resultados: A paciente recuperou-se totalmente da opsoclonia, da mioclonia e da ataxia através de imunoterapia. O artigo também fornece um resumo atualizado sobre a síndrome de opsoclonia-mioclonia-ataxia. Conclusão: Adultos com síndrome de opsoclonia-mioclonia-ataxia têm uma baixa frequência de sequelas residuais. O diagnóstico e o tratamento precoces podem levar a melhores prognósticos. Espera-se que a imunoterapia combinada reduza a incidência da síndrome de opsoclonia-mioclonia-ataxia refratária e recorrente.

A Case of Paraneoplastic Neurological Syndrome Leading to the Diagnosis of Large Cell Neuroendocrine Carcinoma From Opsoclonus-Myoclonus Syndrome.

Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder characterized by myoclonus, ataxia, and tremors. It can be classified as neoplastic or idiopathic, with small cell lung cancer being commonly associated. Herein, we present a rare case of refractory paraneoplastic neurological syndrome (PNS) caused by large cell neuroendocrine carcinoma (LCNEC), a rare form of non-small cell lung cancer (NSCLC). A 60-year-old otherwise healthy man presented with acute-onset dysarthria, gait instability, and numbness on the right side of his body. According to the clinical symptoms and neurological examination, we initially suspected cerebellar infarction; however, brain imaging revealed no abnormal findings. After a few days, the patient developed worsening horizontal nystagmus, irregular ocular rhythms, and generalized involuntary movements, indicative of OMS. A systemic evaluation revealed a solitary nodule in the lower lobe of the right lung, leading to a clinical diagnosis of PNS. The patient underwent segmentectomy to treat an early-stage LCNEC nodule after one month from onset. Despite all therapeutic interventions, OMS was refractory, and after consulting with the person himself and the family, palliative care was selected. However, the patient showed a clinical response belatedly five months after surgery. This case highlights the importance of considering PNS, and that it may be associated with a rare malignancy when cerebellar symptoms are observed, and the challenges in managing refractory PNS associated with rare forms of NSCLC.

Cervical Ganglioneuroblastoma Diagnosed by 68Ga-DOTATOC PET/CT in a Child with Opsoclonus Myoclonus Syndrome.

We performed a 68Ga-DOTATOC PET/CT scan on a 25-mo-old female patient who presented with opsoclonus myoclonus ataxia syndrome and had negative initial anatomic imaging. The scan showed a somatostatin receptor-overexpressing cervical tumor in favor of a cervical neuroendocrine tumor, with subsequent histopathologic findings of ganglioneuroblastoma.

Neuroblastoma-related severe hypoperfusion in the cerebellum of an infant: A case of opsoclonus-myoclonus syndrome.

A 2-year-old girl started to wobble without any specific triggers, so the patient was admitted to our hospital's pediatric department. The entire cerebellum showed severe atrophy on MRI and much lower uptake than that in the cerebral cortex on perfusion SPECT. The diagnosis of opsoclonus-myoclonus syndrome (OMS) was suspected. MRI visualized a small mass behind the inferior vena cava. Although its uptake on I-123 MIBG scintigraphy was inconclusive, the mass was surgically removed, and the diagnosis of neuroblastoma was pathologically confirmed. OMS is one of the paraneoplastic neurological syndromes with cerebellar ataxia, myoclonus of the trunk and extremities, and opsoclonus as its main symptoms. Approximately 50% of children cases with OMS are associated with neuroblastoma. The prognosis for neuroblastoma itself with OMS is relatively good, but the neurological prognosis is very poor. If there is decreased blood flow in the cerebellum of an infant, it may be necessary to search for neuroblastoma.

Presence of identical B-cell clone in both cerebrospinal fluid and tumor tissue in a patient with opsoclonus-myoclonus syndrome associated with neuroblastoma.

Opsoclonus-myoclonus syndrome associated with neuroblastoma (OMS-NB) is a refractory paraneoplastic syndrome which often remain neurological sequelae, and detailed pathogenesis has remained elusive. We encountered a pediatric patient with OMS-NB treated by immunosuppressed therapy who showed anti-glutamate receptor δ2 antibody and increased B-cells in cerebrospinal fluid (CSF), and multiple lymphoid follicles containing abundant Bcells in tumor tissue. Unbiased B-cell receptor repertoire analysis revealed identical B-cell clone was identified as the dominant clone in both CSF and tumor tissue. These identical B-cell clone may contribute to the pathogenesis of OMS-NB. Our results could facilitate the establishment of pathogenesis-based treatment strategies for OMS-NB.

Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). CASE PRESENTATION: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. CONCLUSIONS: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Comparison of mediastinal and non-mediastinal neuroblastoma and ganglioneuroblastoma associated with opsoclonus-myoclonus syndrome: a systematic review and meta-analysis.

Background: Neuroblastoma is the most common malignancy in children younger than seven years of age and is the most frequent extracranial solid tumor that occurs in childhood. While opsoclonus-myoclonus syndrome (OMS), a paraneoplastic neurologic syndrome, affects 2-3% of children with neuroblastoma, and the percentage of mediastinal localization of the tumor is 49%. The objective of this study was to identify and characterize features of the OMS syndrome and treatments of mediastinal and non-mediastinal neuroblastoma associated with OMS. Methods: A systematic review of the literature was performed using PubMed, Medline, Web of Science, Embase and Cochrane. The search has no limit on date with the last search done on Dec 31, 2020. There is no publication restrictions or study design filters applied in the search. Results: Fifty-five out of 242 papers were identified and met our study eligibility. There were 77 cases found (28 cases had Mediastinal neuroblastoma, and 49 cases had non-mediastinal neuroblastoma). Data from trials showed that cases with mediastinal neuroblastoma who seemed to have undergone less treatment for OMS [rate ratio (RR) 0.41 (95% CI: 0.22-0.76)] had resulted in decreasing persistent neurologic symptoms [RR 0.31 (95% CI: 0.10-0.96)]. Conclusions: Children who have OMS and mediastinal neuroblastoma may be associated with more favorable clinical and biological characteristics and better outcomes than children who have OMS and non-mediastinal neuroblastoma, and they are more likely to present with a single neurological symptom at first. The OMS in mediastinal neuroblastoma might also be treated effectively through resection of the tumor followed by appropriate radiotherapy and chemotherapy, and no long-term treatments of OMS is indicated.

Breast Cancer Presenting As Onconeural Antibody Negative Opsoclonus-Myoclonus Syndrome.

Breast cancer can rarely present with or be preceded by paraneoplastic syndromes such as opsoclonus-myoclonus syndrome (OMS). OMS is a rare neurological syndrome that commonly presents with symptoms of rapid, chaotic eye movements (opsoclonus), jerking involuntary muscle movements (myoclonus) and is frequently associated with ataxia. We describe a case of a woman in her early 50s who presented to the emergency room (ER) with vertigo, jerking movements, loss of fine motor skills and gait abnormalities. She was initially thought to have likely vestibular neuritis and was treated symptomatically and discharged home. However, the symptoms persisted and she presented once again to the ER, at which time she also incidentally discovered a lump in her breast. This led to her being investigated more extensively leading to a diagnosis of underlying primary breast cancer. Based on her neurological clinical findings, she was diagnosed with onconeural antibody negative OMS. Treatment of her underlying malignancy led to a significant improvement in her symptoms. Paraneoplastic neurological syndromes (PNSs) are an important differential diagnosis to consider in patients presenting with persistent, treatment-resistant and non-specific neurological symptoms. Any suspicion of the same should prompt a search for an underlying malignancy that could greatly influence patient outcomes.

Síndrome de opsoclonia mioclonia idiopático: Reporte de caso en una paciente de 13 meses / Idiopathic opsoclonus myoclonus syndrome: Case report in a 13-month-old female patient

Resumen El síndrome de opsoclonia mioclonía es una entidad neurológica poco frecuente que afecta a los niños en la etapa preescolar. Clínicamente se caracteriza por una triada clásica de opsoclonía, mioclonía y ataxia aguda, con una evolución progresiva o incluso de manera incompleta. Su etiología puede ser paraneoplásica, en la mayoría de los casos en asociación con neuroblastomas, así como postinfecciosa o parainfecciosa, autoinmune o idiopática. En objetivo del tratamiento es la inmunomodulación con terapia de primera línea con esteroides endovenosos aunque pudiendo asociarse a recaídas y secuelas a largo plazo en el ámbito neurológico y conductual. El síndrome de opsoclonia mioclonía representa un reto diagnóstico en los pacientes con ataxia aguda dada la variedad de presentación clínica, por tanto es importante tener una alta sospecha diagnostica para garantizar un tratamiento oportuno y evitar secuelas futuras.

Abstract Opsoclonus myoclonus syndrome is a rare neurological entity affecting preschool children. Clinically it is characterized by a classic triad of opsoclonus, myoclonus, and acute ataxia, with a progressive or even incomplete course. Its etiology can be paraneoplastic, in most cases in association with neuroblastomas, as well as postinfectious or parainfectious, autoimmune or idiopathic. The goal of treatment is immunomodulation with first-line therapy with intravenous steroids, although it can be associated with relapses and long-term neurological and behavioral sequelae. The opsoclonus myoclonus syndrome represents a diagnostic challenge in patients with acute ataxia given the variety of clinical presentations, therefore it is important to have a high diagnostic suspicion to ensure timely treatment and aoid future sequelae.

Paraneoplastic syndrome in neuroophthalmology.

Paraneoplastic syndrome is a group of clinical symptoms that occur in the state of systemic malignant tumors. Paraneoplastic syndrome of the nervous system can affect any part of the central and peripheral nervous system and may also affect the eyes. In neuroophthalmology, paraneoplastic syndrome has a variety of manifestations that can affect both the afferent and efferent visual systems. The afferent system may involve the optic nerve, retina and uvea; the efferent system may involve eye movement, neuromuscular joints or involuntary eye movements and pupil abnormalities and may also have other neurological symptoms outside the visual system. This article discusses the clinical manifestations, pathological mechanisms, detection methods and treatment methods of paraneoplastic syndrome in neuroophthalmology. The performance of paraneoplastic syndrome is diverse, the diagnosis is difficult, and the treatment should be considered systematically. Differential diagnosis, optimal evaluation and management of these manifestations is not only the key to treatment but also a challenge.

Long-term neurological outcomes of children with neuroblastoma with opsoclonus-myoclonus syndrome.

Background: Neuroblastoma with opsoclonus-myoclonus syndrome (OMS-NB) is a rare disease in children. Few studies of long-term outcome of children with OMS-NB were conducted. This study aimed to review the rate of recovery of neurological symptoms and the long-term neurological outcomes of children with OMS-NB. Methods: This study retrospectively assessed 14 children with OMS-NB diagnosed at Peking University First Hospital from May 2011 to November 2019. Demographic data, neurological symptoms, oncological status and treatments were retrospectively reviewed from the records. Neurological sequelae were recorded by clinical and remote follow-up. Results: During the acute stage, myoclonus and ataxia were observed in all children while opsoclonus was observed in 10/14 children. The median durations of neurological symptoms were 15 months (range, 5-48 months). Approximately 93% (13/14) children revealed neurological sequelae. Significant correlations were as follows: motor retardation with female gender (P<0.001) and residual tumors (P<0.05); language impairment with non-adrenal-gland-located tumors (P<0.05). There were no obvious factors that had a statistical relationship with cognitive disorder or behavioral changes. Conclusions: Children with OMS-NB have favorable outcomes in terms of neurological symptoms. Neurological sequelae occurred in almost all children. Children with different features tend to reveal different sequalae. Features of female gender and residual tumors tend to reveal motor retardation while that of non-adrenal-gland-located tumors tend to reveal language impairment.

Paraneoplastic Opsoclonus-myoclonus Syndrome with Anti-Hu and Anti-SOX-1 Antibodies after Immune-checkpoint Inhibitor Treatment Combined with Chemotherapy in a Patient with Small-cell Lung Cancer.

A 69-year-old man with advanced small-cell lung cancer achieved partial remission after 3 courses of immunochemotherapy that included atezolizumab. Ten days after the last treatment, he developed paraneoplastic opsoclonus-myoclonus syndrome and required mechanical ventilation. Serology testing detected anti-Hu and anti-SOX-1 antibodies. Despite steroid pulse therapy, various anticonvulsants, continuous intravenous sedation, and a fourth course of chemotherapy without atezolizumab, his condition failed to improve. Paraneoplastic opsoclonus-myoclonus syndrome with autoantibodies after immune-checkpoint inhibitor treatment has not been reported previously. Although a causal relationship between immune-checkpoint inhibitors and paraneoplastic syndromes has been suggested, the mechanism remains unknown.

Case Report: Opsoclonus-Myoclonus Syndrome Associated With Contactin-Associated Protein-Like 2 and Acetylcholine Receptor Autoantibodies in the Setting of Non-Small Cell Lung Carcinoma.

Opsoclonus myoclonus syndrome (OMS) is a rare immune-mediated paraneoplastic or para/-post-infectious syndrome characterized by "dancing" eye movements, myoclonus, and ataxia. Neuropsychiatric symptoms have also been reported. Without treatment, OMS may progress to further neurological impairment and even death. Autoimmune attack of CNS structures in OMS is most commonly mediated by anti-Ri (also known as ANNA2) IgG antibodies, with additional findings implicating antibodies targeting various neurotransmitter receptors. Prompt immunotherapy and neoplasm treatment may result in improvement. We report a novel association of Contactin-Associated Protein-Like 2 (Caspr2) antibodies occurring in association with paraneoplastic OMS. While breast cancer and small cell lung cancer (SCLC) are more commonly associated with OMS among adults, we characterize a novel association between Caspr2 antibody in a patient with mixed non-small cell and small cell lung carcinoma.

Opsoclonus Myoclonus Syndrome in a Case of Severe Acute Malnutrition in Children: A Case Report.

Opsoclonus myoclonus syndrome (OMS) is a rare (1 in 10 million people per year) but nonfatal autoimmune disorder characterized by involuntary oscillating eye movements, multifocal muscular jerky movements, severe ataxia, and neuropsychological and behavioral changes. It usually manifests as a paraneoplastic condition but has other etiologies also. To the best of our knowledge, this is the first case of OMS seen in a patient with severe acute malnutrition (SAM). Parents brought a three-year-old female child with complaints of being unable to sit, stand, and hold her neck for the past 18 months. The patient has had involuntary eyeball movements for three months and has shown regression in milestones. Our study aimed to understand the pathophysiology, etiology, and clinical course of OMS in a child with SAM. However, relapses and long-term developmental sequelae are common due to the lack of a common consensus regarding therapeutic guidelines.