Multiple ring-enhancing lesions of the brainRK Garg, MK Sinha
Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
Multiple ring-enhancing lesions of the brain are one of the most commonly encountered abnormalities on neuroimaging. These can be caused by a variety of infectious, neoplastic, inflammatory or vascular diseases. Distinguishing non-neoplastic causes from neoplastic lesions is extremely important because a misdiagnosis can lead to unwarranted neurosurgery and exposure to toxic chemotherapy or potentially harmful brain irradiation. Diligent clinical evaluation and a battery of tests are required for making a definitive diagnosis. Newer advanced diagnostic techniques, such as diffusion-weighted magnetic resonance imaging (MRI), perfusion-weighted MRI, magnetic resonance spectroscopy, single-photon emission tomography and positron emission tomography may help in establishing the etiology. However, early brain biopsy is often needed because several of these diseases are potentially life-threatening.
Keywords: Brain tumor, metastasis, neurocysticercosis, neuroimaging, tuberculoma
Multiple ring-enhancing lesions are one of the most commonly encountered neuroimaging abnormalities [Figure 1]. Widely available imaging techniques, computed tomography and magnetic resonance imaging (MRI) are used to detect these lesions. A wide range of etiologies may present as cerebral multiple ring-enhancing lesions. , On neuroimaging, these lesions appear as hypodense or isodense mass lesions on non-contrast computed (plain) tomography studies. After contrast administration, there is a ring- or a homogeneous disk-like enhancement within the region of hypodensity. The enhancing lesions are often of variable size and are usually surrounded by a varying amount of perifocal vasogenic edema. Typically, the ring-enhancing lesions are located at the junction of the gray and white matter, but they could be located in the sub-cortical area, deep in the brain parenchyma or may even be superficial. 
Clinically, they manifest as recurrent seizures, visual impairment, focal neurological deficit and raised intracranial pressure (severe headache, vomiting and papilledema). If cerebral edema is severe, patients may develop loss of sensorium and posturing of limbs because of transtentorial brain herniation. Intractable headache, focal neurological deficits and vision loss are long-term sequelae in few of the surviving patients.
An extensive review of the literature, published in English, was carried out using the PubMed and Google Scholar databases. The search terms such as multiple ring-enhancing lesions of the brain, tuberculoma, neurocysticercosis, neurological complications of human immunodeficiency virus (HIV) infection, brain tumor, brain metastasis and fungal granuloma were used. This review was written with the objective of evolving a diagnostic approach for these patients.
Diseases causing multiple ring-enhancing lesions of the brain are infectious, neoplastic, inflammatory or vascular in origin. Several types of primary and secondary brain neoplasms, such as glioblastomas, low-grade gliomas, lymphomas and brain metastases can also present as multiple ring-enhancing lesions. Many non-neoplastic neurological disorders can mimic brain neoplasms on neuroimaging. These diseases include tuberculosis, cysticercosis, demyelinating disorders, pyogenic abscess, toxoplasmosis, fungal infections, neurosyphilis, sarcoidosis, Behcet disease, radiation encephalopathy, cerebral venous thrombosis and several other vasculitic disorders [Table 1] and [Table 2]. , A variety of free-living amebas Naegleria, Balamuthia mandrillaris and Acanthamoeba are unusual causes of central nervous system (CNS) infections presenting as multiple ring-enhancing lesions of the brain. All these parasites are known to produce multiple ring-enhancing lesions of the brain.
Schwartz et al. reviewed 221 ring-enhancing lesions seen on MRI studies and reported that 40% were gliomas, 30% metastases, 8% abscesses and 6% demyelinating disease. In a majority of the cases, gliomas and metastatic lesions were single whereas abscesses and multiple sclerosis lesions were multiple. Metastatic deposits are often solid nodular lesions that may become ring-enhancing possibly because of central necrosis. In this study, multiple cortical or subcortical ring-enhancing lesions have also been encountered in patients with subacute bacterial endocarditis, indwelling catheters or other implanted devices such as cardiac valves. Deep white matter ring-enhancing lesions, especially those with mass effect and surrounding vasogenic edema, are most often either primary brain tumors or abscesses.  In developing and poor countries, the spectrum of etiologies of multiple ring-enhancing lesions of the brain is likely to be different as infective pathologies are more frequently encountered. 
Primary and metastatic tumors, on imaging, often manifest as rounded, well-circumscribed, ring-enhancing lesions of variable sizes surrounded by a variable amount of perifocal vasogenic edema.
Metastatic tumors are the most common intracranial neoplasm in adults. Lung cancer, breast cancer and melanoma account for the majority of patients with metastasis in the brain [Figure 2]. The incidence of brain metastases has recently increased because of several factors, including improved survival, better treatment of systemic diseases and improved intracranial imaging techniques.  In a large study, 200 consecutive patients with clinical suspicion of metastatic carcinoma and signs of cerebral dysfunction were evaluated by computed tomography. In 10 patients, computed tomography identified a non-neoplastic disease, whereas in 190, computed tomography discovered a metastatic lesion. In 70 patients, the metastatic brain lesion was solitary while in 120 patients the lesions were multiple. In 52 patients, non-contrast computed tomography showed a solitary lesion but contrast computed tomography revealed multiple lesions. In nine patients, the abnormality was seen only on contrast computed tomography. There were no characteristic computed tomography patterns for specific systemic carcinomas, but epidermoid carcinoma frequently appeared as a low-density lesion with a thin peripheral enhancing rim, and adenocarcinoma appeared as a dense, homogeneous, round, enhancing nodule. After treatment, focal cerebral parenchymal enhancement was the most reliable sign of residual or recurrent tumor. 
Metastatic lesions are typically subcortical, occurring in or near the gray matter-white matter junction, and are usually associated with severe perilesional edema. MRI typically reveals mild T1 hypointensity with T2 hyperintensity and fluid-attenuated inversion recovery hyperintensity at the site of the lesion. After contrast administration, a nodular ring pattern of enhancement is seen. Metastases from malignant melanoma may demonstrate T1 hyperintensity because of hemorrhagic or melanin components of the lesion. 
Rapidly growing primary brain tumors, such as glioblastoma multiforme or anaplastic astrocytoma, can present with many of the same imaging characteristics as seen in metastatic lesions of the brain. Most of the primary tumors are large in size and are often located deep in the white matter.  Primary brain tumors frequently cross the midline. For example, glioblastoma multiforme frequently crosses the midline by infiltrating the white matter tracts of the corpus callosum.
Patients with metastatic brain tumors may require surgical resection, whole-brain radiation therapy and/or other treatment options such as radiosurgery. Most of the primary brain tumors are difficult to treat. The current standard treatment for primary brain tumors includes surgical resection followed by a combination of radiation and chemotherapy.
Pyogenic brain abscesses may, at times, be multiple. Multiple brain abscesses are often caused by hematogenous spread of bacteria from a primary source and are frequently found in the territory of the middle cerebral artery. The likely sources of primary infection in patients with multiple brain abscesses include cyanotic heart disease, endocarditis, suppurative lung diseases, skin infection and abdominal and pelvic infections. Multiple pyogenic brain abscesses are common in patients with human immunodeficiency virus infection, organ transplant recipients, intravenous drug abuse, chemotherapy for lymphoma, congenital cardiac defects or prosthetic cardiac valves and diabetes.
The enhancing ring lesions caused by pyogenic brain abscesses are commonly located at the gray-white matter junction. Frequently, the capsule of abscess is difficult to visualize via conventional imaging techniques and double-contrast computed tomography is needed to clearly define the capsule of the abscess. On non-contrast MRI, pyogenic abscess show an isointense-to-slightly-hyperintense capsule on T1-weighted images, and is hypointense on T2-weighted images. The ring enhancement on post-contrast images is usually thin and smooth and often thinner along the medial margin. However, greater thickness, irregularity and nodularity of the wall of the lesions are often suggestive of tumor or a fungal infection.
Tuberculomas are frequently encountered brain lesions in tropical countries. Intracranial tuberculoma can occur with or without tuberculous meningitis. Numerous small tuberculomas are common in patients with miliary pulmonary tuberculosis. A non-caseating tuberculoma usually appears hyperintense on T2-weighted and slightly hypointense on T1-weighted images. A caseating tuberculoma appears iso- to hypointense on both T1-weighted and T2-weighted images, with an iso- to hyperintense rim on T2-weighted images. Tuberculomas on contrast administration appear as nodular or ring-like enhancing lesions.  The diameter of these enhancing lesions usually ranges from 1 mm to 5 cm. Tuberculomas frequently show varied types of enhancement, including irregular shapes, ring-like shapes, open rings and lobular patterns. Target-like lesions are common. Pre-contrast, the magnetization transfer MRI helps in assessing the disease load in patients with CNS tuberculosis. A higher number of tuberculomas is seen on the magnetization transfer magnetic resonance images compared with routine spin echo images.  Magnetization transfer MRI has also been found to be effective in the reliable differentiation of tuberculomas from cysticercus granuloma [Figure 3].
Neurocysticercosis is the most common parasitic disease of the CNS and is a major cause of seizures worldwide. After reaching inside the brain parenchyma, the cysticercus larva passes through several stages of evolution. Initially, the cyst consists of a protoscolex surrounded by a bladder wall. This stage of viable cyst is known as vesicular cyst stage. The living viable cyst evokes only a minimal inflammatory reaction. At this stage, the scolex usually is identified as an eccentric nodule within the cyst. In the next stage, the cyst wall gets thickened and hyaline degeneration and mineralization of the cyst take place. The cyst fluid becomes opaque. These degenerating cysts are called colloid cyst stage. In this stage, there is an intense inflammatory reaction in the surrounding brain tissue. In this stage, neuroimaging reveals contrast enhancing ring or disc lesions. It is thought that the immunologic process elicited by the release of dying parasite antigens is responsible for clinical manifestations of neurocysticercosis. Thereafter, the wall of the cyst thickens and the scolex is transformed into coarse mineralized granules. This stage, in which the cysticercus is no longer viable, is called the granular nodular stage. When the cysticercus dies, the bladder wall collapses to form a small granuloma. Months to years later, some of these dead cysts get calcified into small nodules. This stage is called calcific stage.
In endemic regions, diagnosis of neurocysticercosis may be difficult because several other infective diseases have similar clinical and neuroimaging manifestations. Specific criteria have been laid down to facilitate accurate diagnosis of neurocysticercosis  [Table 3].
On MRI, the wall of the cysticercus granuloma (a colloid cyst stage) becomes thick and hypointense and there is marked perilesional edema on T2-weighted images. Cysticercus granuloma shows a ring pattern of enhancement after contrast medium administration. Usually, the lesions are <20 mm in diameter. Calcified eccentric scolex is often seen in a cysticercal lesion. The lesions are often multiple and most often do not have extensive edema. ,
Multiple enhancing ring lesions are encountered in several acute demyelinating disorders. Enhancing demyelinating lesions differ in size, shape or pattern. Most of them demonstrate a nodular pattern. Some of them demonstrate a ring-enhancing pattern and few have other patterns. None of the neuroimaging patterns just described are specific for multiple sclerosis or other acute demyelinating disorders. The only exception to this is an open ring or incomplete ring lesion. Presence of an open ring or incomplete ring lesion helps in differentiating demyelinating lesions from large brain tumors or infective lesions like brain abscess. Demyelinating lesions, including both classic multiple sclerosis and tumefactive demyelination, may also create an open ring or incomplete ring sign. Patients with atypical ring-enhancing lesions and mass effect usually undergo brain biopsy to establish the diagnosis. Otherwise, biopsy of these lesions is not indicated because conservative medical treatment with corticosteroids results in a favorable outcome in most of the cases. ,
Intracranial mass lesions are among the common neurologic complications of HIV infection. These lesions are frequently encountered in advanced stages of HIV infection. The nature of the HIV-associated intracranial mass lesions falls into three distinct categories - opportunistic infections, neoplasms and cerebrovascular diseases. The common causes include toxoplasmosis, tuberculoma and primary CNS lymphoma and, rarely, brain abscess and fungal granuloma.
Occurrence of mass lesions of the brain depends on a variety of factors, including treatment with highly active antiretroviral drugs and the patient's level of immunosuppression. An HIV-infected patient is at a high risk of developing opportunistic infections of the brain (often manifesting as multiple enhancing lesions) when the CD4+ count is <200 cells/μL.
Toxoplasmosis is a common cause of multiple intracranial mass lesions in patients with acquired immunodeficiency syndrome (AIDS). It occurs in 3-10% of patients with AIDS in the United States and in up to 50% of the patients in Europe and Africa. For an immuno-suppressed patient who presents with focal neurologic signs and multiple ring-enhancing lesions of the brain on imaging, cerebral toxoplasmosis would be the most likely diagnosis, and current guidelines suggest that all such patients be treated with antitoxoplasma treatment. After approximately 2 weeks of treatment, a decrease in the number and size of lesions with reduction in edema should be observed. Combination of pyrimethamine/sulfadiazine and folinic acid is considered the standard regime for the treatment of cerebral toxoplasmosis. Empirical treatment for toxoplasmosis should be started when the patient presents with multiple ring-enhancing lesions, positive serology for toxoplasma antibodies and absolute CD4+ count <200 cells/mm 3 . A lack of response to such therapy should alert the clinician about the possibility of other conditions such as CNS lymphoma or progressive multifocal leukoencephalopathy. The characteristic imaging pattern in toxoplasmosis lesions is a ring-enhancing lesion made up of an eccentric nodule. In around 30% of the lesions, this enhancing nodule is found within and adjacent to the enhancing rim.  Most lesions in toxoplasmosis occur in basal ganglia and in frontal and parietal lobes.
Primary CNS lymphoma is second most common cause of intracranial mass lesions in HIV infected patients. It occurs in up to 2.0% of HIV-infected patients and appears to be increasing in incidence, possibly as a consequence of improved survival. 
The lesions of primary CNS lymphoma on computed tomography are hyperintense or isointense, round or oval masses with homogeneous contrast enhancement and variable surrounding edema. They are often multifocal and periventricular in location. Leptomeningeal involvement may be seen. Lymphomatous lesions are frequently periventricular and have indistinct borders. The lymphomas rarely invade the basal ganglia and have a tendency to occur in the white matter adjacent to an ependymal surface. Approximately 50% of the patients with CNS lymphoma may also have multifocal ring-enhancing lesions. 
Several unusual pathogens like Nocardia asteroids rarely cause multiple intracerebral abscesses in immunocompromised patients. Brain aspergillosis is also a rare fungal infection of the CNS and is responsible for multiple cerebral septic infarctions and abscess formations.  Other causes of multiple ring-enhancing lesions of the brain in patients with HIV infection, include tuberculous abscesses and tuberculomas, cryptococcal abscesses and cryptococcomas, syphilitic gummas, Candida abscesses and other infectious disorders, metastatic tumors and cerebrovascular diseases.
The fungal granuloma may present as multiple brain abscesses. Fungal abscesses are mainly located in the brain stem, basal ganglia and cerebral cortex of the frontal, parietal and occipital lobes; cerebellar and spinal locations are uncommon. Fungal infections of the CNS are rare in the general population. They are most frequently encountered in immunocompromised patients such as those with HIV infection or after organ transplantation. Several varieties of fungi may cause granulomatous lesions in the brain. The most common fungus that produces granulomatous lesions in the brain is Aspergillus. Aspergillus flavus is generally implicated as the causative organism in patients who are immunocompetent whereas A. fumigatus is more frequently reported in immunocompromised individuals. Several other fungi also cause multiple enhancing lesions in the brain.
Neuroimaging in patients with fungal granuloma reveals multiloculated thick walls with a necrotic core. Fungal granulomas frequently reveal a ring-like or nodular enhancement on MRI and cannot be distinguished from granuloma of other etiology. On non-contrast MRI, the ring of the fungal granuloma is irregular and of low signal on T2-weighted MRI images. , Intracavitary projections seen inside an abscess cavity are considered characteristic of fungal abscesses. These intracavitary projections have been confirmed as fungal hyphae on histopathologic examination of the wall of the excised abscess. 
Evaluation of a patient's history, findings of physical examination and laboratory data are crucial for making the diagnosis in patients with multiple enhancing lesions of the brain [Table 4] and [Table 5]. The differential diagnosis of multiple ring-enhancing lesions depends on the age and the immune status of the patient. In the immunocompetent host, malignancies (both primary and metastatic) and pyogenic abscesses remain the most likely diagnoses in patients with large-sized lesions. Abscesses caused by atypical microorganisms and demyelinating disease should also be considered in the differential diagnosis of multiple enhancing lesions of the brain. In tropical countries, cysticercus granuloma frequently needs to be differentiated from intracranial tuberculoma. Tuberculomas tend to be larger than 20 mm in diameter, have an irregular outline, cause more mass effect and have a progressive focal neurologic deficit, whereas cysts tend to be <20 mm in diameter, have a smooth regular outline and seldom cause progressive focal neurologic deficits [Table 5]. ,
Attempts have been made to identify the lesion on the basis of distinctive neuroimaging characteristics of ring-enhancing lesions. In general, abscesses are characterized by a thin, uniform ring, which is thinner on the medial border, and with a smoother outer margin; satellite lesions are often present. A thick, irregular, ring-like enhancement suggests a necrotic brain tumor. Some low-grade brain tumors are "fluid-secreting" and may form heterogeneously enhancing lesions. These low-grade brain tumors may present with an incomplete ring sign and may reveal the classic "cyst-with-nodule" morphology.  Multiple enhancing lesions can be seen in patients with multifocal glioma. However, the presence of more than three distinct lesions is unusual for a patient with primary brain tumor. The radiological differential considerations for a cystic tumor with an enhancing mural nodule include pilocytic astrocytoma, hemangioblastoma, pleomorphic xanthoastryocytoma, meningioma and ganglioglioma. These benign brain tumors rarely present as multiple enhancing lesions. Demyelinating lesions, including both classic multiple sclerosis and tumefactive demyelination, may present with an open ring or incomplete ring sign, and are often misdiagnosed as brain neoplasms.
In HIV-infected patients, the leading causes of multiple enhancing lesions are toxoplasmosis and primary CNS lymphoma. Imaging characteristics that are helpful in distinguishing toxoplasmosis from CNS lymphoma include subcortical gray matter location of toxoplasmosis lesions, their multiplicity, presence of eccentric target sign and enhancing wall of the lesions thinner than that observed in lymphomas. Thick and irregular periventricular enhancement is typical for primary CNS lymphoma. Corpus callosum involvement is infrequent in primary CNS lymphoma. Furthermore, the immunocompromised patients are at risk for abscesses, from both pyogenic and atypical organisms, and tumors. Tuberculomas and tuberculous brain abscess should be considered in endemic regions in both immunocompetent and immunocompromised hosts. Because of the low sensitivity of Mycobacterium tuberculosis cultures or polymerase chain reaction detection of mycobacterial DNA from cerebrospinal fluid, diagnosis of intracranial tuberculoma is often difficult. Several patients may remain undiagnosed despite extensive evaluation. ,
Several algorithms have been designed with the objective to differentiate varied etiologies of ring-enhancing lesions of the brain. Unfortunately, most of these are of limited usefulness for the patients of resource-poor countries. The limited usefulness of these algorithms are due to, firstly, the fact that these are based upon scarcely available newer diagnostic techniques.  Secondly, the spectrum of etiology is different in India and other of resource-poor countries than that of developed countries. The algorithms provided in this article are based on clinical evaluation and routinely employed diagnostic tests [Figure 4] and [Figure 5].
Several new neuroimaging modalities such as diffusion-weighted MRI, perfusion-weighted MRI, magnetic resonance spectroscopy, single-photon emission tomography and positron emission tomography as well as newer methods for histological examination, such as immunohistochemistry and molecular genetics analysis, allow reliable differentiation between neoplastic causes of multiple enhancing lesions of the brain from various non-neoplastic causes , [Table 5].
Many recent studies have shown that diffusion-weighted imaging is a sensitive and specific method in differentiating brain abscesses from brain tumor. A cerebral abscess cavity shows a hyperintense signal on diffusion-weighted images and a hypointense signal on apparent-diffusion-coefficient images, indicating the presence of an area of restricted diffusion.  Pus in the abscess cavity is associated with high cellularity and viscosity, which contributes to a decrease in the water proton mobility, resulting in restriction of diffusion. On the contrary, cystic brain tumors have central areas of hypointense signal on diffusion-weighted imaging unless there is a hemorrhagic or proteinaceous component, which may appear as an area of heterogeneous or bright signal. ,
Magnetic resonance perfusion is another non-invasive imaging method that is often used in the diagnosis of multiple ring-enhancing lesions of the brain. Several studies support the utility of this method, alone or in combination with others, for differentiating various focal mass lesions. For example, high regional cerebral blood volume values in the peripheral areas appear to indicate the possibility of a necrotic brain tumor whereas low values indicate an abscess. 
Magnetic resonance spectroscopy determines the concentration of brain metabolites such as N-acetyl aspartate, choline, creatine and lactate in the brain tissue. This technique may be helpful in differentiating tumor from infective pathologies and abscesses (e.g., presence of choline peak in tumor, amino acid peak in abscesses, acetate and succinate peaks in abscesses and parasitic cysts) when considered along with other magnetic resonance findings. This method can also help in the identification of the causative organism of the mass lesions of the brain. Trehalose is a disaccharide that occurs naturally in insects, plants, fungi and bacteria. A high concentration of alpha, alpha-trehalose has been demonstrated in cryptococcomas. In a magnetic resonance spectroscopy study, the authors have demonstrated trehalose in the fungal abscess wall.  Tuberculoma and tuberculous show prominent lipid peaks without significant elevations of other peaks.  Another important finding in magnetic resonance spectroscopic studies is glutamate/glutamine peaks in demyelinating disorders. Because elevation of these peaks is typically not seen in intra-axial neoplastic processes, it helps in differentiating neoplasm from demyelination. This point is important because tumefactive demyelinating lesions often mimic intracranial neoplasm. 
Several reports have suggested that thallium-201 single-photon emission computed tomography may help to differentiate intracranial tumors from other non-neoplastic diseases. The utility of Thallium-201 single-photon emission computed tomography is limited. Some authors consider thallium-201 single-photon emission computed tomography useful in this differentiation when interpreted in association with MRI findings. 
Positron emission tomography can provide useful information regarding the metabolism of a brain lesion, which may be useful for differentiating neoplastic lesions from infective lesions like brain abscess. Tumors typically show increased metabolic activity in the center of the lesion, whereas abscesses do not. At times, in a high-grade brain tumor that often has a necrotic center, the reduced metabolic activity in the center of the malignant tumor can make it difficult to differentiate it from the pattern found in brain abscess. Thus, positron emission tomography has limited specificity in distinguishing between neoplastic and non-neoplastic ring-enhancing intracerebral lesions. , Differentiating a tumor recurrence from radiation necrosis can be difficult. It has been suggested that positron emission tomographic study can be used to distinguish between radiation necrosis and tumor. 
Most of the available non-invasive methods have a limited role to play in establishing the definitive diagnosis in patients with multiple ring-enhancing lesions of the brain. Frequently, early biopsy is generally considered essential because a majority of the deferential diagnosis are life threatening if left untreated. Biopsy of undiagnosed multiple ring-enhancing lesion lesions should preferably be performed stereotactically to minimize tissue injury.
The American Academy of Neurology guidelines for the management of patients with AIDS suggests that ring-enhancing lesion in the setting of negative toxoplasmosis serology requires early biopsy. Otherwise, a trial of pyrimethamine and sulfadiazine is required for the treatment of presumptive toxoplasmosis.  In poor and developing countries, where neurosurgical services are scantly available, histopathological confirmation is often not possible and treatment of toxoplasmosis often remains empirical.
Multiple ring-enhancing lesions of the brain remain a diagnostic challenge. These lesions are frequently caused by common non-neoplastic and neoplastic disorders. There are numerous reports available revealing an unusual pathogen or an infrequent variety of tumor presented with multiple ring-enhancing lesions of the brain. Often, diagnostic challenge is stiffer than expected, and exact diagnosis is not forthcoming even after clinical evaluation and a battery of tests. In a majority of such cases, brain biopsy of the brain lesions remains the only option to establish early diagnosis.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]