RESUMEN
BACKGROUND: The unique neurovascular structure of the retina has provided an opportunity to observe brain pathology in many neurological disorders. However, such studies on neurodegeneration with brain iron accumulation (NBIA) disorders are lacking. OBJECTIVES: To investigate NBIA's neurological and ophthalmological manifestations. METHODS: This cross-sectional study was conducted on genetically confirmed NBIA patients and an age-gender-matched control group. The thickness of retinal layers, central choroidal thickness (CCT), and capillary plexus densities were measured by spectral domain-optical coherence tomography (SD-OCT) and OCT angiography, respectively. The patients also underwent funduscopy, electroretinography (ERG), visual evoked potential (VEP), and neurological examination (Pantothenate-Kinase Associated Neurodegeneration-Disease Rating Scale [PKAN-DRS]). The generalized estimating equation model was used to consider inter-eye correlations. RESULTS: Seventy-four patients' and 80 controls' eyes were analyzed. Patients had significantly decreased visual acuity, reduced inner or outer sectors of almost all evaluated layers, increased CCT, and decreased vessel densities, with abnormal VEP and ERG in 32.4% and 45.9%, respectively. There were correlations between visual acuity and temporal peripapillary nerve fiber layer (positive) and between PKAN-DRS score and disease duration (negative), and scotopic b-wave amplitudes (positive). When considering only the PKAN eyes, ONL was among the significantly decreased retinal layers, with no differences in retinal vessel densities. Evidence of pachychoroid was only seen in patients with Kufor Rakeb syndrome. CONCLUSION: Observing pathologic structural and functional neurovascular changes in NBIA patients may provide an opportunity to elucidate the underlying mechanisms and differential retinal biomarkers in NBIA subtypes in further investigations. © 2023 International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedades Neurodegenerativas , Neurodegeneración Asociada a Pantotenato Quinasa , Humanos , Estudios Transversales , Potenciales Evocados Visuales , Retina/diagnóstico por imagen , Retina/patología , Encéfalo , Enfermedades Neurodegenerativas/patología , Tomografía de Coherencia Óptica , HierroRESUMEN
BACKGROUND: Retinal biomarkers in neurodegenerative disorders have attracted much attention in recent years. Recent studies have reported visual dysfunction in Huntington's disease (HD). However, little is known about retinal structural changes in HD. METHODS: A total of 50 subjects, including 25 motor-manifest HD patients and 25 gender- and age-matched controls, were enrolled. Unified Huntington's Disease Rating Score-Motor part was assessed in HD patients. Spectral-domain Optical Coherence Tomography (SD-OCT) was used to evaluate the macular thickness and peripapillary retinal nerve fiber layer (pRNFL). Superficial and deep capillary plexus densities were measured using OCT angiography (OCTA). To account for inter-eye correlation, generalized estimating equation (GEE) model was used. RESULTS: HD patients had a significant reduction in macular thickness in both inner and outer superior sectors and the inferior outer sector. Inferior pRNFLs were significantly decreased in thickness. There was no significant difference in retinal capillary plexus density between the two groups. Age and disease duration were negatively correlated with macular thickness in HD patients. However, the severity of motor involvement was not correlated with SD-OCT or OCTA parameters. CONCLUSIONS: We observed attenuated pRNFL and macular retinal thickness in patients with HD, independent of macular capillary plexus parameters. It can support the hypothesis that the retina may be a potential biomarker for monitoring the neurodegenerative process in HD.
Asunto(s)
Enfermedad de Huntington , Fibras Nerviosas , Biomarcadores , Humanos , Enfermedad de Huntington/diagnóstico por imagen , Retina/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodosRESUMEN
Background: During the COVID-19 pandemic, elderly individuals (with the chronological age of 65 years and above) are more susceptible to the SARS-CoV-2 infection complications due to altered immune system response and the higher rate of underlying comorbidities. A vast majority of mortalities are reported in elderly patients; thus, this study aimed to evaluate complications of COVID-19 in elderly patients. Methods: A systematic review was conducted according to MOOSE guidelines. Science Direct, Google Scholar, Scopus, PubMed databases were searched for published articles related to COVID-19 in the elderly up to March 26, 2020. Search MeSh terms included "Severe acute respiratory syndrome coronavirus 2", "2019-nCoV", "SARS-CoV-2", "comorbidity", "elderly", and "geriatrics". Results: In total 1360 potentially relevant articles were screened, of which 35 were relevant and their full texts were considered for the review. Organ damages to the pulmonary system, cardiovascular, liver, and renal system are more prevalent in the elderly with SARS-CoV-2 infection. As the chance of multiorgan involvement is more common among elderly patients, preventive, multidisciplinary, and holistic evaluations are essential to reduce disease consequences. Conclusion: More attention needs to be paid to elderly individuals in the quarantine. Social contact should be made and maintained through online facilities, media, and phone calls to ensure patients' mental health during this stressful situation. Also, they should be provided with enough food and medications by their families or friends. Also, providing social and volunteer services might play an important role in the mental health of those patients who have no social network.
RESUMEN
Behavioral, electrophysiological, and imaging data reveal impaired visual processing and altered retinal morphology in Parkinson disease. Are visual changes epiphenomena? We report the presence of misfolded α-synuclein in the retina, not hitherto shown, in discrete retinal neurons within the inner retina. They demonstrate the histopathology that may underlie impaired vision and retinal remodeling in Parkinson disease. Furthermore, the histological localization of α-synuclein gives clues to the nonsynaptic mode of α-synuclein propagation.
Asunto(s)
Enfermedad de Parkinson/patología , Retina/metabolismo , Retina/patología , alfa-Sinucleína/metabolismo , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Optical coherence tomography offers a potential biomarker tool in Parkinson's disease (PD). A mathematical model quantifying symmetry, breadth, and depth of the fovea was applied. METHODS: Nintey-six subjects (72 PD and 24 healthy controls) were included in the study. Macular scans of each eye were obtained on two different optical coherence tomography devices: Cirrus and RTVue. RESULTS: The variables corresponding to the cardinal gradients of the fovea were the most sensitive indicators of PD for both devices. Principal component analysis distinguished 65% of PD patients from controls on Cirrus, 57% on RTVue. CONCLUSION: Parkinson's disease shallows the superior/inferior and to a lesser degree nasal-temporal foveal slope. The symmetry, breadth, and depth model fits optical coherence tomography data derived from two different devices, and it is proposed as a diagnostic tool in PD.
Asunto(s)
Fóvea Central/patología , Enfermedad de Parkinson/patología , Retina/patología , Anciano , Biomarcadores , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Índice de Severidad de la Enfermedad , Tomografía de Coherencia ÓpticaRESUMEN
Restless legs syndrome (RLS) is a common sleep disorder that can present secondary to medical conditions such as renal failure. This study aimed to evaluate RLS frequency and its related factors in chronic renal failure patients treated with hemodialysis. In a cross-sectional design, 163 patients with chronic renal failure were consecutively enrolled from hemodialysis center at Rasool-Akram hospital. Demographics, clinical and laboratory data were recorded. Patients were screened for presence and severity of RLS according to the four International Restless Legs Syndrome Group (IRLSSG) diagnostic criteria and severity scale. Patients with and without RLS were compared using SPSS statistical software (Version 16.0). Sixty-one patients (37.4 %) were diagnosed with RLS. Mean age in RLS group was significantly higher (65.2 ± 9.3 years) than RLS-negative group (59.0 ± 14.7 years; P = 0.004). Serum creatinine level was significantly higher in patients with RLS (7.6 ± 2.1 mg/dl vs. 6.7 ± 1.8 mg/dl; P = 0.009). Glomerular filtration rate in RLS patients was lower than other patients (9.2 ± 3.1 ccs/min vs. 11.6 ± 4.8 ccs/min; P = 0.0001). Patients with RLS had shorter sleep duration, and higher incidence of insomnia, daytime sleepiness, and sedative-hypnotic medication usage (P < 0.05). There was no significant difference between RLS-positive and RLS-negative patients in terms of renal failure pathology, dialysis frequency per week, dose of dialysis, duration of dialysis, renal transplantation, and history of diabetes and hypertension. Hemodialysis patients have a high prevalence of RLS which deserves special attention and specific treatment.
Asunto(s)
Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Diálisis Renal/métodos , Síndrome de las Piernas Inquietas/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Tasa de Filtración Glomerular , Humanos , Irán/epidemiología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The development of optical coherence tomography (OCT) has led to increasing interest in the retina in Parkinson's disease (PD). The retina is a multilayered tissue: looking into the eye from the outside, these layers comprise the nerve fiber layer (NFL); the ganglion cell layer (GCL); the inner plexiform layer (IPL), which contains the interconnecting plexus, including tyrosine hydroxylase-positive (dopaminergic) fibers of amacrine cells; the inner nuclear layer; and several outer retinal layers. Commercial spectral-domain OCT has a specific program for detecting peripapillary NFL defects and a different macular program for diabetic retinopathy. Specific programs for PD are not commercially available. Taking all studies together, it seems that macular programs have a higher diagnostic yield than NFL programs, but the numbers of studies and examined patients are relatively small. It is not certain that all retinal thinning in PD is due to dopaminergic neuronal loss. When applying OCT, the where (region of interest) and the what of the focus of automated programs must be considered. With these caveats, one could take advantage of the power of OCT for looking in-depth into the terra incognita of individual retinal layers at the fovea and perhaps at other appropriate retinal locations.
Asunto(s)
Enfermedad de Parkinson/patología , Retina/patología , Humanos , Tomografía de Coherencia ÓpticaRESUMEN
Spectral-domain Optical coherence tomography (OCT) has shown remarkable utility in the study of retinal disease and has helped to characterize the fovea in Parkinson disease (PD) patients. We developed a detailed mathematical model based on raw OCT data to allow differentiation of foveae of PD patients from healthy controls. Of the various models we tested, a difference of a Gaussian and a polynomial was found to have "the best fit". Decision was based on mathematical evaluation of the fit of the model to the data of 45 control eyes versus 50 PD eyes. We compared the model parameters in the two groups using receiver-operating characteristics (ROC). A single parameter discriminated 70 % of PD eyes from controls, while using seven of the eight parameters of the model allowed 76 % to be discriminated. The future clinical utility of mathematical modeling in study of diffuse neurodegenerative conditions that also affect the fovea is discussed.
Asunto(s)
Fóvea Central/patología , Modelos Teóricos , Enfermedad de Parkinson/patología , Retina/patología , Tomografía de Coherencia Óptica/métodos , Tomografía de Coherencia Óptica/estadística & datos numéricos , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
Little is known about the results of pallidal deep brain stimulation (DBS) in DYT6 dystonia. This will be the first report of DYT6 dystonia treated with pallidal DBS from Iran. A 21 years old male patient with DYT6 dystonia underwent bilateral deep brain stimulation. The target of DBS was the sensorimotor region of the posteroventral globus pallidus internus (GPi). DBS parameters included an amplitude of 2.7 V, frequency of 160 Hz, and pulse width of 90 µs which were adjusted according to the patient's response 12 months after surgery. Treatment outcome was measured by the patient's Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) score. Before surgery, the patient's BFMDRS score was 32. However, BFMDRS score reduced to 7 at one year follow up after surgery (78% improvement of total score). Dystonic symptoms of extremities and mouth completely resolved. Also speech and swallowing function significantly improved. Although previous observations reported a poor to moderate response in speech, we found DBS as an effective treatment not only for dystonic features, but also for speech improvement of DYT6 dystonia.
RESUMEN
BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is recommended as a promising technique for the management of the primary generalized dystonia (PGD) with DYT1 gene mutation. We present the first report of DBS results in Iranian patients with DYT1 positive PGD. METHODS: Nine patients who suffered from severely disabling DYT1 positive PGD consecutively were recruited for the study between 2008 and 2010. The patients underwent bilateral deep brain stimulation of the GPi in a single procedure. The mean follow up duration was 8.8 ± 2.2 months. The efficacy of the intervention was evaluated by comparing pre- and post operative scores of patients with Burke-Fahn-Marsden's dystonia Scale (BFMDS). Statistical analysis was performed using SPSS 11.0 software. RESULTS: Of 9 patients six were female with the mean age of 15.2 ± 5.5 years old (range: 8- 25 years old). The mean for Burke-Fahn-Marsden's Dystonia Rating Scale (BFMDRS) score was 47.22 ± 14.1 before surgery and 12.3 ± 8.2 after follow up, which significantly improved (P=0.0001).The mean stimulation parameters at the last visit were at a frequency of 152.2 ± 32.4 Hz (range 130- 230 Hz), a voltage of 2.6 ± 0.7 V (range 1.1- 4), and a pulse width of 60 µsec. No complication was observed during follow up. CONCLUSION: Bilateral DBS of the GPi has an encouraging result for the management of DYT1 positive PGD and is recommended as a safe technique for the treatment of these patients. Shorter pulse width in stimulation parameters is suggested for DYT1 dystonia patients.
RESUMEN
Restless legs syndrome (RLS) is a common neurological movement disorder that is often seen in multiple sclerosis patients. However, the association between RLS and multiple sclerosis (MS) is still unclear and RLS is not considered as one of the MS symptoms. This study was conducted to assess the frequency of RLS and its associated factors in patients with MS. This was a cross-sectional study conducted during January and April 2010. A total of 205 patients diagnosed with multiple sclerosis (164 females, 41 males, mean age 32.8 ± 8.9 years) were enrolled in the study and underwent a medical history interview and a neurological examination. The diagnosis of RLS was based on International Restless Legs Syndrome Study Group Criteria. 57 patients (27.8%) met the RLS diagnostic criteria. In 90.1% of the patients, the onset of RLS was simultaneous with or followed by MS onset. There was no significant difference between patients with and without RLS in respect of age, gender, disease duration, and MS pattern. There was an increased incidence of leg jerks before sleep in patients with RLS (P = 0.04). In patients suffering from RLS, there is greater complaint of insomnia (P = 0.03). Body mass index, history of anemia, excessive day-time somnolence, consuming caffeine-containing beverages, pregnancy numbers, smoking, and alcohol consumption were not associated with the presence of RLS. This study revealed high prevalence of RLS in MS patients. Screening of RLS in these patients should always be considered to improve management of MS.
Asunto(s)
Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/epidemiología , Síndrome de las Piernas Inquietas/diagnóstico , Síndrome de las Piernas Inquietas/epidemiología , Adulto , Estudios Transversales , Femenino , Humanos , Irán/epidemiología , Masculino , Adulto JovenRESUMEN
Objective: To describe a case of optic neuropathy after prolonged sirolimus therapy in the setting of cardiac transplant. Background: Sirolimus is an immunosuppressant that inhibits Mechanistic Target of Rapamycin (mTOR) and blocks T-cell activation and B-cell differentiation by preventing response to Interleukin-2 (IL-2). Tacrolimus is another immunosuppressive agent, one of the known but uncommon side effects of which is bilateral optic neuropathy years after taking the medication. To the best of our knowledge, this is the first report of sequential optic neuropathy after years of treatment with sirolimus. Case Presentation: A 69-year-old male with a history of cardiac transplantation presented with progressive, sequential, and painless vision loss. Visual acuity was 20/150 OD and 20/80 OS, with impaired color vision in both eyes (Ishihara 0/10) and bilateral disc pallor and mild optic disc edema in the left eye. Visual field was constricted in both eyes. The patient was on prolonged sirolimus therapy for over 7 years. Orbital MRI revealed bilateral chiasmatic thickness and FLAIR hyperintensity, without optic nerve enhancement post gadolinium. After extensive work up, other etiologies such as infectious, inflammatory, and neoplastic lesions were ruled out. Subsequently, sirolimus was substituted with cyclosporin that led to gradual improvement of vision and visual fields bilaterally. Conclusion: Optic neuropathy is a rare side effect of tacrolimus, which has been seen as sudden, painless, and bilateral vision loss in post-transplant patients. Other concurrent medications influencing the cytochrome P4503A enzyme complexes may alter the pharmacokinetics of tacrolimus and increase the likelihood of toxicity. Discontinuation of offending agent has been shown to improve visual defects. We presented a rare case of optic neuropathy in a patient on sirolimus, whose visual defects improved upon discontinuation of sirolimus and switching to cyclosporin.
RESUMEN
Purpose: We report a case of a 10-year-old with Moring glory disc anomaly (MGDA) associated with Moyamoya disease and pituitary stalk duplication. Observations: A 10-year-old Asian child presented with decreased vision in the right eye and bilateral nystagmus. Both dilated fundus exam and magnetic resonance imaging (MRI) of the orbit confirmed MGDA of the right eye. MRI of the brain demonstrated duplication of the pituitary stalk. Magnetic resonance angiography (MRA) of the brain revealed bilateral severe narrowing (greater on the right side) of the distal supraclinoid internal carotid arteries with bilateral reconstitution at the carotid terminus and prominent collaterals, suggestive of Moyamoya disease. Conclusions: Patients with MGDA should undergo neuroimaging due to the associated central nervous system (CNS) anomalies.
RESUMEN
Idiopathic intracranial hypertension (IIH) has an increasing incidence worldwide over the past decade, with a high economic burden on patients and society. Up to 10% of patients with IIH have progressive visual decline requiring an invasive intervention (including cerebrospinal fluid shunting, cerebral dural sinus stenting, or optic nerve sheath fenestration [ONSF]). IIH patients with visual decline usually undergo evaluation and initial management through the emergency department (ED) and commonly have a long hospital stay due to the lack of a dedicated methodology for evaluation and management, particularly in patients who present with visual loss (i.e., fulminant IIH). An innovative practice approach is needed to improve the means of multidisciplinary communication in care and evaluation of IIH patients. This paper aims to discuss the need for the development and implementation of a multidisciplinary "fast-track" strategy for the evaluation and management of patients with fulminant IIH or those with a suboptimal response to maximum tolerated medical treatment at risk for visual loss. We suggest that such a program could reduce hospital stay and ED visits and therefore reduce healthcare costs and improve patient outcomes by accelerating the management process.
RESUMEN
OBJECTIVE: To determine the longitudinal changes in retinal microstructure, microvasculature, microcirculation, and axonal and neuronal functions in patients with relapsing-remitting multiple sclerosis (RRMS) over the time course of about two years. METHODS: A total of 30 patients (60 eyes) with RRMS were followed for a period of 27 ± 6 months and evaluated with a battery of clinical tests including low contrast letter acuity (LCLA), intraretinal layer thicknesses by optical coherence tomography (OCT), ganglion cell function by steady-state pattern electroretinography (PERG), axonal function by polarization-sensitive OCT, volumetric vessel density (VVD) by OCT angiography, and retinal tissue perfusion (RTP) by retinal function imager. RESULTS: Axonal function measured as retinal nerve fiber layer birefringence in the temporal quadrant and vessel density in the deep vascular plexus were significantly decreased at 2-year follow-up (P < 0.05). Subgroup analyses showed that the increased retinal blood flow volume occurred in patients with no evidence of disease activity (NEDA), and with stable or improved visual function (P < 0.05). There was no significant difference in the expanded disability state scale, LCLA, RTP, VVD, or PERG measures between the two visits (P > 0.05). CONCLUSION: To our best knowledge, this is the first 2-year prospective comprehensive study with a detailed assessment of retinal microstructure and neuronal functions in patients with RRMS. The recovery of retinal microcirculation occurred in patients with NEDA, and stable or improved visual function, suggesting these measurements as potential imaging biomarkers for monitoring disease progression.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Estudios de Seguimiento , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Estudios Prospectivos , Retina/diagnóstico por imagen , Tomografía de Coherencia ÓpticaRESUMEN
BACKGROUND: Impaired vision and remodeled foveal pit have been demonstrated in Parkinson's disease (PD) patients using different techniques. METHODS: Ten PD (20 eyes) and eight healthy controls (HC) subjects (16 eyes) were enrolled. Subjects were evaluated for N70 and P100 latencies using two-channel VEP with pattern reversal and on/off pattern; Contrast sensitivity (CS) using Pelli-Robson chart; macular thickness measured using Zeiss-HD optical coherence tomography (OCT). RESULTS: PD patients had a significantly delayed N70 (reversal pattern) and P100 (on/off pattern), lower CS score, and decreased retinal thickness at temporal 1.5-2.5 mm from the foveola. N70 latency was negatively correlated with CS (R = -0.419, P = 0.01) and average GCL-IPL thickness (R = -0.529, P = 0.001). CS was positively correlated with parafoveal thickness (R = 0.490, P = 0.002). A combination of parafoveal thickness and CS score yielded an AUC of 0.784 for PD discrimination which increased to 0.844 when combined with N70 and P100 measures. CONCLUSION: A combination of pattern reversal VEP latency, CS score, and inner retinal foveal thickness measures has a high diagnostic yield for PD.
Asunto(s)
Potenciales Evocados Visuales/fisiología , Enfermedad de Parkinson/diagnóstico , Estimulación Luminosa/métodos , Retina/patología , Tomografía de Coherencia Óptica/métodos , Anciano , Sensibilidad de Contraste/fisiología , Estudios Transversales , Electrodiagnóstico/métodos , Femenino , Fóvea Central/patología , Fóvea Central/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Retina/fisiopatologíaRESUMEN
Inner foveal thinning and intracellular alpha-synuclein were demonstrated in the retina in Parkinson disease. While pathognomonic alpha-synuclein is associated with embryonic dopaminergic (DA) neurons, postmortem studies in the nervous system and retina show prominent effect also in non-DA neurons. We evaluated foveal capillaries and foveal thickness in 23 Parkinson disease subjects and 13 healthy controls using retinal fluorescein angiography and optical coherence tomography. The size of the foveal avascular zone inversely correlates with foveal thinning. Foveal thinning highly correlates with motor impairment and also disease duration. Quantifying capillary and neuronal remodeling could serve as biological markers.
RESUMEN
BACKGROUND: Restless legs syndrome (RLS) is the most common movement disorder in pregnancy, which can be idiopathic or secondary. There are limited comparative data regarding these two forms of RLS. The aim of this study was to compare clinical features of idiopathic and secondary RLS in pregnant women. METHODS: Over a period of 3 months, 443 women who admitted for delivery in two clinical centers were screened for RLS using four diagnostic criteria of the international RLS study group. A total of 79 subjects diagnosed with RLS were consecutively enrolled in the present study. All of them were interviewed for medical history and complaints during pregnancy and responded to self-administer international RLS rating scale. RESULTS: Ten subjects (12.9%) out of 79 pregnant women with RLS had idiopathic form, and their mean age was significantly higher than patients with secondary RLS (30.6 ± 7.3 years vs. 26.4 ± 4.6 years, P = 0.0260). Compared with women with secondary RLS, sleep duration in pregnancy was significantly decreased in idiopathic RLS group (P = 0.0460), whereas RLS severity score was similar in both groups. No significant difference was observed between the two groups in terms of other sleep complaints, the positive family history of RLS, parity, duration of pregnancy, or frequency of cesarean section (P > 0.0500). CONCLUSION: Idiopathic and secondary RLS have relatively similar courses and features during pregnancy. However, the idiopathic form may have more negative impact on sleep in pregnancy. Careful screening and effective treatment of idiopathic RLS before pregnancy is recommended to limit these disturbances.
RESUMEN
Pseudoaneurysms of superficial temporal artery are very rare and commonly occur as a result of blunt trauma. There are several methods for the diagnosis, but the diagnosis can be accurately made only from a history and physical examination. A 27-year-old man presented with a painless pulsatile mass over his right temporal region after a blunt head trauma. The diagnosis was suspected to be superficial temporal artery pseudoaneurysm. The patient underwent surgical exploration and the mass was resected. Histopathological findings confirmed the diagnosis of pseudoaneurysm. Superficial temporal artery pseudoaneurysm can be easily diagnosed through an accurate history and physical examination alone. Diagnostic methods can be used in complicated cases.