Transcranial sonography in differential diagnosis of Parkinson disease and other movement disorders / 中华医学杂志(英文版)

BACKGROUND@#Reports evaluating the efficacy of transcranial sonography (TCS) for the differential diagnosis of Parkinson disease (PD) and other movement disorders in China are scarce. Therefore, this study aimed to assess the application of TCS for the differential diagnosis of PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and essential tremor (ET) in Chinese individuals.@*METHODS@#From 2017 to 2019, 500 inpatients treated at the Department of Dyskinesia, Beijing Tiantan Hospital, Capital Medical University underwent routine transcranial ultrasound examination. The cross-sections at the midbrain and thalamus levels were scanned, and the incidence rates of substantia nigra (SN) positivity and the incidence rates of lenticular hyperechoic area were recorded. The echo of the SN was manually measured.@*RESULTS@#Of the 500 patients, 125 were excluded due to poor signal in temporal window sound transmission. Among the 375 individuals with good temporal window sound transmission, 200 were diagnosed with PD, 90 with ET, 50 with MSA, and 35 with PSP. The incidence rates of SN positivity differed significantly among the four patient groups (χ2 = 121.061, P  0.017).@*CONCLUSION@#SN positivity could effectively differentiate PD from ET, PSP, and MSA in a Chinese population.

A Cortical Substrate for Square-Wave Jerks in Progressive Supranuclear Palsy

Combined Assessment of Serum Alpha-Synuclein and Rab35 is a Better Biomarker for Parkinson's Disease

BACKGROUND AND PURPOSE: It is essential to develop a reliable predictive serum biomarker for Parkinson's disease (PD). The accumulation of alpha-synuclein (αSyn) and up-regulated expression of Rab35 participate in the etiology of PD. The purpose of this investigation was to determine whether the combined assessment of serum αSyn and Rab35 is a useful predictive biomarker for PD. METHODS: Serum levels of αSyn or Rab35 were determined in serum samples from 59 sporadic PD patients, 19 progressive supranuclear palsy (PSP) patients, 20 multiple system atrophy (MSA) patients, and 60 normal controls (NC). Receiver operating characteristics (ROC) curves were calculated to determine the diagnostic accuracy of αSyn or/and Rab35 in discriminating PD patients from NC or atypical parkinsonian patients. RESULTS: The levels of αSyn and Rab35 were increased in PD patients. The serum level of Rab35 was positively correlated with that of αSyn in PD patients. Compared to analyzing αSyn or Rab35 alone, the combined analysis of αSyn and Rab35 produced a larger area under the ROC curve and performed better in discriminating PD patients from NC, MSA patients, or PSP patients. When age was dichotomized at 55, 60, 65, or 70 years, the combined assessment of αSyn and Rab35 for classifying PD was better in the group below the cutoff age than in the group above the cutoff age. CONCLUSIONS: Combined assessment of serum αSyn and Rab35 is a better biomarker for discriminating PD patients from NC or atypical parkinsonian patients, and is a useful predictive biomarker for younger sporadic PD patients.

No Evidence of a Contribution of the Vestibular System to Frequent Falls in Progressive Supranuclear Palsy

BACKGROUND AND PURPOSE: Conflicting results about vestibular function in progressive supranuclear palsy (PSP) prompted a systematic examination of the semicircular canal function, otolith function, and postural stability. METHODS: Sixteen patients with probable PSP [9 females, age=72±6 years (mean±SD), mean disease duration=3.6 years, and mean PSP Rating Scale score=31] and 17 age-matched controls were examined using the video head impulse test, caloric testing, ocular and cervical vestibular evoked myogenic potentials (o- and cVEMPs), video-oculography, and posturography. RESULTS: There was no evidence of impaired function of the angular vestibulo-ocular reflex (gain=1.0±0.1), and caloric testing also produced normal findings. In terms of otolith function, there was no significant difference between PSP patients and controls in the absolute peakto-peak amplitude of the oVEMP (13.5±7.2 µV and 12.5±5.6 µV, respectively; p=0.8) or the corrected peak-to-peak amplitude of the cVEMP (0.6±0.3 µV and 0.5±0.2 µV, p=0.3). The total root-mean-square body sway was significantly increased in patients with PSP compared to controls (eyes open/head straight/hard platform: 9.3±3.7 m/min and 6.9±2.1 m/min, respectively; p=0.032). As expected, the saccade velocities were significantly lower in PSP patients than in controls: horizontal, 234±92°/sec and 442±66°/sec, respectively; downward, 109±105°/sec and 344±72°/sec; and upward, 121±110°/sec and 348±78°/sec (all p<0.01). CONCLUSIONS: We found no evidence of impairment of either high- or low-frequency semicircular function or otolith organ function in the examined PSP patients. It therefore appears that other causes such as degeneration of supratentorial pathways lead to postural imbalance and falls in patients with PSP.

Increased Signal in the Superior Cerebellar Peduncle of Patients with Progressive Supranuclear Palsy

OBJECTIVE: The provisional diagnosis of progressive supranuclear palsy (PSP) depends on a combination of typical clinical features and specific MRI findings, such as atrophy of the tegmentum in the midbrain. Atrophy of the superior cerebellar peduncle (SCP) distinguishes PSP from other types of parkinsonism. Histological factors affect the conventional fluid-attenuated inversion recovery (FLAIR) signals, such as the extent of neuronal loss and gliosis. METHODS: We investigated patients with PSP to verify the percentage of patients with various PSP phenotypes presenting a high signal intensity in the SCP. Three interviewers, who were not informed about the clinical data, visually inspected the presence or absence of a high signal intensity in the SCP on the FLAIR images. We measured the pixel value in the SCP of each patient. Clinical characteristics were evaluated using the Mann-Whitney test, followed by the χ² test. RESULTS: Ten of the 51 patients with PSP showed a high signal intensity in the SCP on FLAIR MRI. Higher pixel values were observed within the SCP of patients with a high signal intensity in the SCP than in patients without a high signal intensity (p < 0.001). The sensitivity and specificity of the high signal intensity in the SCP of patients with PSP was 19.6% and 100%, respectively. This finding was more frequently observed in patients with PSP with Richardson's syndrome (PSP-RS) (25.7%) than other phenotypes (6.2%). CONCLUSION: The high signal intensity in the SCP on FLAIR MRI might be an effective diagnostic tool for PSP-RS.

Clinical Milestones Preceding the Diagnosis of Multiple System Atrophy and Progressive Supranuclear Palsy: A Retrospective Cohort Study

OBJECTIVE: Multiple System Atrophy (MSA) and progressive supranuclear palsy (PSP) are rapidly progressive forms of degenerative Parkinsonism. The difficulties of diagnosing MSA and PSP in their early stages may lead to delayed referral to appropriate specialists and distress to patients, as well as delaying symptomatic treatment and participation in clinical trials. This work aimed to describe the symptoms that patients with MSA and PSP developed and plot their emergence relative to final diagnosis using a median onset in months. METHODS: Forty-seven patients from the United Kingdom with MSA or PSP diagnosed by a movement disorder specialist were interviewed with carers or relatives to establish milestone onset. This was corroborated using clinical notes and letters. RESULTS: In the MSA cohort (n = 23), autonomic symptoms (median 5.5 months before diagnosis) and falls (median 1 month before diagnosis) were the two clinical milestones which occurred before diagnosis. In the PSP cohort (n = 24), falling was the only milestone which occurred before diagnosis (median of 18.5 months). CONCLUSION: This study shows that PSP patients experience falling more than a year and a half an average before receiving a diagnosis and although MSA patients also tended to fall, this was much closer to the time of diagnosis. Further work with larger cohorts may illustrate whether these preliminary findings can be generalised to guide diagnosis and management.

Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies / 대한핵의학회잡지

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.

Prospective Characterization of Cognitive Function in Typical and ‘Brainstem Predominant'Progressive Supranuclear Palsy Phenotypes

OBJECTIVE: Clinicopathological studies over the last decade have broadened the clinical spectrum of progressive supranuclear palsy (PSP) to include several distinct clinical syndromes. We examined the cognitive profiles of patients with PSP-Richardson's syndrome (PSP-RS) and two atypical ‘brainstem predominant' PSP phenotypes (PSP-parkinsonism, PSP-P; and PSP-pure akinesia with gait freezing, PSP-PAGF) using a comprehensive neuropsychological battery. METHODS: Fourteen patients diagnosed as PSP-RS, three patients with PSP-P and four patients with PSP-PAGF were assessed using a comprehensive battery of neuropsychological tests.

Purposeless Groaning in Parkinson's Disease

Purposeless groaning has been reported in advanced progressive supranuclear palsy. We present a case of purposeless groaning occurring as a primary complaint in a patient with advanced Parkinson's disease. Purposeless groaning is thought to be a manifestation of disinhibition and perseveration due to frontal-subcortical dysfunction. Proper recognition of this phenomenon will help clinicians to avoid unnecessary investigations and treatment (e.g., prescription of opioid medications).

Tau Positron Emission Tomography Imaging in Degenerative Parkinsonisms

In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer's disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum. In progressive supranuclear palsy, the globus pallidus and midbrain have shown increased binding most prominently. Tau PET patterns in patients with corticobasal syndrome are characterized by asymmetrical uptake in the motor cortex and underlying white matter, as well as in the basal ganglia. Even in the patients with multiple system atrophy, which is basically a synucleinopathy, ¹⁸F-flortaucipir, a widely used tau PET tracer, also binds to the atrophic posterior putamen, possibly due to off-target binding. These distinct patterns of tau-selective radiotracer binding in the various degenerative parkinsonisms suggest its utility as a potential imaging biomarker for the differential diagnosis of parkinsonisms.

Síndrome da Paralisia Supranuclear Progressiva: As dificuldades de diagnóstico e a atuação da Equipe multidisciplinar quanto aos cuidados à pessoa afetada por esta doença / Progressive Supranuclear Palsy Syndrome: The difficulties of diagnosis and the performance of the Multidisciplinary Team regarding the care of the person affected by this disease / Síndrome de parálisis supranuclear progresiva: Las dificultades de diagnóstico y el trabajo del equipo multidisciplinario sobre el cuidado de la persona afectada por esta enfermedad

A Síndrome da Paralisia Supranuclear Progressiva (PSP) é doença neurodegenerativa do Sistema Nervoso Central (SNC), rara, e de difícil diagnóstico, afetando principalmente o tronco cerebral e os núcleos da base. O quadro clínico se caracteriza por oftalmoparesia supranuclear, instabilidade postural e demência. O objetivo do estudo foi investigar a fisiopatologia, diagnóstico, tratamento e assistência da equipe multidisciplinar às pessoas com PSP. Revisão integrativa de 15 artigos publicados na base de dados da Biblioteca Virtual da Saúde, BVS, envolvendo estudos de casos e pesquisa de campo. O estudo revelou pouca publicação acerca da doença e, por ser rara, não existe fármaco eficiente e eficaz; o diagnóstico é limitado nas primeiras manifestações, e somente possível por meio de exames mecanicistas. Em razão de existir parco material sobre a assistência a estes casos, sugere-se que os Conselhos, Associações de Neurologia e demais especialidades envolvidas no tratamento desenvolvam, divulguem mais detalhes sobre a doença, a fim de se criar um protocolo de atendimento integral aos afetados pela síndrome, bem como o necessário apoio aos familiares e cuidadores, que auxilie nas práticas da assistência ambulatorial e familiar.

Progressive Supranuclear Palsy Syndrome (PSP) is a rare and difficult diagnosis of the central nervous system (CNS) neurodegenerative disease that mainly affects the brainstem and nuclei of the base. The clinical picture is characterized by supranuclear ophthalmoparesis, postural instability and dementia. Objective: to investigate the pathophysiology, diagnosis, treatment and assistance of the multidisciplinary team to PSP users. Integrative review of 15 articles published in the database of the Virtual Health Library, VHL, involving case studies and field research. Results: the study revealed little publication about the disease and, because it is rare, there is no efficient and effective drug; The diagnosis is limited in the first manifestations, and it is only possible by means of mechanistic examinations. Because there is little material on the assistance to these cases, it is suggested that the Neurology Councils and Associations and other specificities involved in the treatment develop and disseminate more details about the disease, in order to create a protocol for comprehensive care Affected by this syndrome, as well as the necessary support for family members and caregivers, to assist in outpatient and family care practices.

Parálisis Supranuclear Progresiva Syndrome (PSP) es una enfermedad neurodegenerativa del sistema nervioso central (SNC), una rara y difícil de diagnosticar, que afecta principalmente el tronco cerebral y los ganglios basales. El cuadro clínico se caracteriza por oftalmoparesia supranuclear, inestabilidad postural y demencia. Investigar la fisiopatología, diagnóstico, tratamiento y atención del equipo multidisciplinario para llevar a la PSP. Revisión integradora de 15 artículos publicados en la Biblioteca Virtual en Salud Base de datos, BVS, que incluye casos de estudio y la investigación de campo. El estudio mostro poca publicación de la enfermedad y, debido a que es raro, no hay ningún fármaco eficaz y eficiente; el diagnóstico es limitada en las primeras manifestaciones, y sólo es posible a través de pruebas mecanicistas. Dado que el material que hay escasa la ayuda a estos casos, se sugiere que las juntas y asociaciones de neurología y otras especilidades implicados en el tratamiento desarrollan y dan a conocer más detalles acerca de la enfermedad, de manera que se crea un protocolo de tratamiento integral para afectadas por este síndrome, así como el apoyo necesario a las familias y cuidadores para ayudar en las prácticas de atención ambulatoria y la familia.

‘Hummingbird’ Sign in a Patient with Guam Parkinsonism-Dementia Complex

We present a case of a 71-year-old male Chamorro patient from Guam who presented with progressive supranuclear palsy (PSP)-Richardson’s syndrome. Considering his strong family history of parkinsonism and a PSP phenotype, he was clinically diagnosed with Guam parkinsonism-dementia complex (PDC). Magnetic resonance imaging (MRI) of the brain revealed prominent midbrain atrophy with preserved pontine volume, forming the ‘hummingbird’ sign, which has not been described before in Guam PDC. Molecular analysis of the chromosome 9 open reading frame 72 gene (C9orf72) showed only 6 GGGGCC repeats. We discuss the clinico-pathological similarities and differences between PSP and Guam PDC, and highlight the topography of neuropathological changes seen in Guam PDC to explain the appearance of the ‘hummingbird’ sign on MRI.

Progressive Supranuclear Gaze Palsy with Predominant Cerebellar Ataxia: A Case Series with Videos

Progressive supranuclear palsy (PSP) with predominant cerebellar ataxia (PSP-C) is a rare phenotype of PSP. The clinical and radiological features of this disorder remain poorly characterized. Through a retrospective case series, we aim to characterize the clinical and radiological features of PSP-C. Four patients with PSP-C were identified: patients who presented with prominent cerebellar dysfunction that disappeared with the progression of the disease. Supranuclear gaze palsy occurred at a mean of 2.0 ± 2.3 years after the onset of ataxia. Mild cerebellar volume loss and midbrain atrophy were detected on brain imaging, which are supportive of a diagnosis of PSP. Videos are presented illustrating the co-existence of cerebellar signs and supranuclear gaze palsy and the disappearance of cerebellar signs with disease progression. Better recognition and the development of validated diagnostic criteria would aid in the antemortem recognition of this rare condition.

Presentación de una paciente portadora de parálisis supranuclear progresiva / Presentation of a patient carrying a progressive supra-nuclear paralysis

La parálisis supranuclear progresiva o síndrome Steele-Richardson-Olszewsky, es una enfermedad rara, degenerativa, producida por el deterioro y muerte gradual de áreas selectas del cerebro. Se presentó el caso de una paciente femenina, de 80 años de edad, que refiere inestabilidad postural, caídas frecuentes y trastornos de memoria anterógrada, unida a trastornos cognitivos. Además, presenta rigidez nucal en retrocolis y caída de ambos párpados, temblor de la mano izquierda, lenguaje disártrico e incoherente, y temblor de ambas manos en cuenta monedas. El examen cardiovascular mostró 2º ruido aumentado, soplo sistólico III/VI en foco mitral, TA 160/90 mm de Hg, edemas en ambos miembros inferiores, frecuencia cardíaca 110 latidos/min, ingurgitación yugular. El resto del examen físico fue normal. El diagnóstico etiológico fue: parálisis supranuclear progresiva y cardiomiopatía dilatada. Se discutió que la proteína tau es importante en el mantenimiento de la morfología neuronal a través de la formación de microtúbulos, las diferentes proporciones, localizaciones, causando el síndrome Richardson. La sintomatología más común de esta entidad es la inestabilidad del postural y caídas frecuentes disartria, bradiquinesia y alteraciones visuales. La resonancia magnética y la neuroimagen funcional ayudan al diagnóstico.

The progressive supra-nuclear paralysis (PSP) or Steele-Richardson-Olszewsky’s syndrome is a strange, degenerative illness produced by the deterioration and gradual death of brain selected areas. We present the case of a female patient, aged 80 years, who refers postural instability, frequent falls and cognitive dysfunctions. She also presents stiffness in retrocollis in the back of the neck, fall of eyelids, left hand shaking, dysarthric and incoherent language, and shaking of both hands in coins counting. The cardiovascular examination showed 2nd increased beat, systolic murmur III/IV in mitral focus, AT 160/90 mm of Hg, edemas in both inferior members, hearth frequency of 110 beats/min., and jugular ingurgitation. The rest of the physical examination was normal. The etiologic diagnosis was progressive supranuclear paralysis and dilated cardiomyopathy. The tau protein is important in the maintenance of the neuronal morphology through microtubules formation, the different proportions and locations, causing the Richardson’s syndrome. The most common symptoms of this entity are postural instability and frequent falls, dysarthria, hypokinesia and visual alterations. Magnetic resonance and functional neuroimaging help the diagnosis.

Clinical Approach to Progressive Supranuclear Palsy

Sixty years ago, Steele, Richardson and Olszewski designated progressive supranuclear palsy (PSP) as a new clinicopathological entity in their seminal paper. Since then, in addition to the classic Richardson's syndrome (RS), different clinical phenotypic presentations have been linked with this four-repeat tauopathy. The clinical heterogeneity is associated with variability of regional distribution and severity of abnormal tau accumulation and neuronal loss. In PSP subtypes, the presence of certain clinical pointers may be useful for antemortem prediction of the underlying PSP-tau pathology. Midbrain atrophy on conventional MRI correlates with the clinical phenotype of RS but is not predictive of PSP pathology. Cerebrospinal fluid biomarkers and tau ligand positron emission tomography are promising biomarkers of PSP. A multidisciplinary approach to meet the patients' complex needs is the current core treatment strategy for this devastating disorder.

Progressive Supranuclear Palsy-Like Syndrome after Surgical Repair of Chronic Ascending Aorta Dissection

A 70-year-old woman underwent cardiopulmonary bypass surgery for aorta dissection. After 10 days she developed a vertical gaze palsy, and 2 months later she presented with dysarthria, bradykinesia, postural instability, blepharospasm, and truncal tilt to the left. Brain imaging indicated old lacunes in the bilateral thalamus. Her symptoms remained unchanged during a 4-year follow-up, which seems to be incompatible with progressive supranuclear palsy (PSP). However, the clinical features of this case were suggestive of PSP-like syndrome after cardiopulmonary bypass surgery.

Corticobasal Degeneration Presenting as Non-Fluent/Agrammatic Primary Progressive Aphasia: A Case Report

BACKGROUND: Non-fluent agrammatic primary progressive aphasia (naPPA) is characterized by progressive non-fluent speech disorder and might be associated with taupathy such as corticobasal degeneration (CBD) and progressive supranuclear palsy. We report a case of overlap syndrome presented with language impairment, and diagnosed as naPPA with possible CBD. CASE REPORT: A 58-year-old woman visited a memory and dementia clinic, with a 10-month history of progressive language disturbance. She was diagnosed as naPPA and overlapping CBD, based on the clinical features and neuroimaging findings including florbetaben PET. CONCLUSIONS: naPPA is pathologically caused by taupathy, and might progress to asymmetrical parkinsonism and apraxia, suggestive of CBD. Overlapping clinical features in our case represent various phenotypes of taupathy.

Caídas frecuentes y neuroimágenes en paciente con parálisis supranuclearprogresiva. Presentación de caso y revisión de la literatura / Frequent falls neuroimaging in a patient with progressive supranuclear palsy

Las caídas en los adultos mayores son comunes, peligrosas y frecuentemente incapacitantes. Con frecuenciason multifactoriales y requieren un amplio abordaje diagnóstico. Las demencias, la enfermedad de Parkinsonidiopática (EP), la enfermedad cerebrovascular y las neuropatías se encuentran entre las condiciones neurológicasque con mayor frecuencia se asocian a caídas. Sin embargo, cuando estas se presentan con recurrenciaen el contexto de un síndrome parkinsoniano, particularmente al inicio de la enfermedad, deben sugerir eldiagnóstico de una parálisis supranuclear progresiva (PSP). Esta entidad es de diagnóstico esencialmente clínico;sin embargo, dado su pronóstico sombrío, se realizan imágenes por resonancia magnética (IRM) de cerebro atodos los pacientes para excluir otros diagnósticos alternativos y buscar hallazgos característicos de PSP. Estosson, principalmente, atrofia del mesencéfalo, borramiento de la sustancia nigra, atrofia del putamen y atrofiacon aumento de la señal del globo pálido.Se presenta a continuación el caso de un paciente adulto mayor que presentaba demencia y parkinsonismorefractario a levodopa, con caídas frecuentes, en quien la realización de una resonancia magnética sirvió paraaclarar el diagnóstico al evidenciar los hallazgos típicos de PSP. Además, se hace una breve revisión de losprincipales hallazgos con imágenes, de demencias parkinsonianas, y la prevención de caídas en estos pacientes.

Falls in the elderly are common, dangerous and often disabling. They are often multifactorial and require extensive diagnostic approach. Dementia, Idiopathic Parkinson's Disease, cerebrovascular disease and neuropathies are among the most frequent neurological condictions associated with falls. However, if a patient has had early instability and recurrent falls associated with a Parkinsonian syndrome, particularly at the beginning of the disease, it should suggest the diagnosis of Progressive Supranuclear Palsy (PSP). PSP is essentially a clinical diagnosis, however, given the bleak prognosis, Magnetic Resonance Imaging (MRI) of the brain is performed in all patients to exclude alternative diagnoses and to look for supporting features of PSP. These include signal increase and atrophy of the midbrain, thinning or smudging of the substantia nigra, atrophy of the putamen, atrophy and signal increase of globus pallidus.We present the case of an adult patient who had dementia and parkinsonism refractory to levodopa with frequent falls in whom typical findings of PSP were documented in MRI. In addition, a brief review of the main findings in Parkinsonian Dementias images and fall prevention in these patients.

Longitudinal Clinical Changes of Non-Fluent/Agrammatic Primary Progressive Aphasia as Tau Spectrum Disorder: A Case Report

BACKGROUND: Tauopathies are a group of diseases caused by the accumulation of hyperphosphorylated tau protein in the central nervous system. Previous studies have revealed that there is considerable overlap in clinical, pathological, and genetic features among different taupathies. CASE REPORT: We report a patient with non-fluent/agrammatic primary progressive aphasia at the initial assessment. Over time, other symptoms belonging to corticobasal degeneration and progressive supranuclear palsy appeared in this patient. CONCLUSIONS: Clinical overlapping features in these disorders may represent different phenotypes of a single disease process.