Neurological Emergencies in Cancer and Immunocompromised Patients

Tumoral Hemorrhage

Intracranial hemorrhage occurs in up to 15% of patients with brain tumors and in 57% of such patients presenting with acute neurological syndromes. In cancer patients, hemorrhage most commonly arises from solid tumors and coagulopathies, which are seen in hematologic malignancies and chemotherapy. Mechanisms of tumoral hemorrhage include abnormally friable blood vessels, tumor necrosis, and vascular invasion. Hemorrhage is most commonly intraparenchymal, followed by subarachnoid, intraventricular, subdural, or a combination of all. Melanoma, lung, and breast cancers are the most common primary malignancies to present with hemorrhagic metastases, and long-term anticoagulation confers an increased risk. On CT, hemorrhages at the grey-white matter interfaces and with greater than expected vasogenic edema raise concern for underlying metastases over nontumoral causes such as hypertension or amyloid angiopathy. On MRI, areas of contrast enhancement, mixed signal intensities, and delayed evolution of blood products on serial studies are suspicious for underlying tumor ( Fig. 3.1 ).

Hydrocephalus

Hydrocephalus can lead to increased intracranial pressure and is an important cause of morbidity in patients with intracranial malignancies. Mechanisms include direct mass effect and increased production (e.g., choroid plexus tumors) or decreased resorption of CSF (e.g., elevated CSF protein, hemorrhage, leptomeningeal disease, and possibly radiation-induced fibrosis of arachnoid granulations). Ventricular obstruction is the most common cause of hydrocephalus and is most frequently seen in tumors involving the posterior fossa, brainstem, and pineal region ( Fig. 3.2 ). Hydrocephalus may develop rapidly in tumors with aggressive growth or in those complicated by hemorrhage.

Infections

Immunocompromised patients are susceptible to opportunistic infections from a wide range of microorganisms. In patients with HIV, opportunistic central nervous system (CNS) infections establish a diagnosis of acquired immunodeficiency syndrome (AIDS) and are associated with very low CD4 cell counts (typically below 100/mm ³ ) and increased mortality.

Toxoplasmosis. Toxoplasmosis is caused by Toxoplasma gondii and results from reactivation of a latent infection. T. gondii is a unicellular protozoan that can infect the CNS in severely immunocompromised patients, usually those with HIV and a CD4 count lower than 100/mm ³ . Although toxoplasmosis remains the most prevalent opportunistic infection in HIV, its incidence has decreased due to the widespread adoption of combined antiretroviral therapy (ART) and routine prophylaxis against Pneumocystis jirovecii . Toxoplasmosis leads to necrotic ring-enhancing lesions that are usually multiple and located in the basal ganglia or at grey-white matter junctions. Focal neurologic syndromes are common, and movement disorders are frequently seen when the basal ganglia are involved. Ring-enhancing lesions characteristically present with a peripheral nodule (the “eccentric target” sign) formed by inflamed vessels invaginating into a sulcus. Another distinctive feature is the presence of hypo- and hyperintense concentric rings on T2/FLAIR sequences due to alternating areas of hemorrhage and necrosis ( Fig. 3.3 ). Toxoplasmosis less commonly presents with a diffuse encephalitis.

Fungal infections. Fungal organisms are usually nonpathogenic or lead to limited disease in immunocompetent individuals but are an important cause of morbidity and mortality in immunocompromised hosts. Although invasive fungal infections are commonly seen in AIDS patients and stem cell transplant recipients, they also occur in patients with chronic steroid administration, malignancy, diabetes, indwelling catheters, and intravenous drug use. Cryptococcal meningoencephalitis is the most common CNS fungal infection in immunocompromised hosts, with the majority occurring in AIDS patients with low CD4 counts (<100/mm ³ ). Cryptococcus is an encapsulated yeast found in decaying wood and soil frequented by birds and contaminated by their droppings. Infection is acquired via inhalation and is disseminated hematogenously to the CNS. The yeast demonstrates a high tropism for the meninges and preferentially spreads along the perivascular spaces of the lenticulostriate and thalamo-perforating arteries. Lesions are typically located in the basal ganglia, thalami, and medial cerebellum but can occur anywhere in the brain. On MRI, there may be enhancing granulomatous masses (cryptococcomas) with variable restricted diffusion. Leptomeningeal enhancement is not a prominent feature, and its presence depends on the host’s capacity to mount an immune response. Other findings include gelatinous pseudocysts, choroid plexitis, and hydrocephalus ( Fig. 3.4 ). Between 50% and 70% of patients have increased intracranial pressure and require therapeutic CSF drainage. A normal brain imaging study does not exclude the possibility of cryptococcal infection.

Candida species enter the host via inhalation or by direct inoculation from trauma, surgery, or indwelling catheters. Infection may disseminate hematogenously in immunosuppressed patients, resulting in candidemia. Meningoencephalitis and microabscesses are the most common CNS manifestations, while macroabscesses, mycotic aneurysms, vasculitis, and infarction are rare. Imaging findings of meningitis are nonspecific and may appear as leptomeningeal enhancement and/or sulcal FLAIR hyperintensity; however, MRI can be normal. Candida abscesses may be indistinguishable from pyogenic ones with ring enhancement and central restricted diffusion, although the degree of enhancement varies depending on the host’s immune response. Also, compared with pyogenic abscesses, fungal abscesses have a variable appearance, with intermixed areas of facilitated (rather than restricted) diffusion as well as intracavitary projections ( Fig. 3.5 ).

Invasive fungal species can cause aggressive infections in neutropenic patients with hematologic malignancies, and in those with stem cell transplants mortality reaches 50% to 80%. Angioinvasive fungal infections are associated with high mortality and are most commonly caused by Aspergillus and Mucor species. Immunocompromised individuals are at risk of invasive fungal rhinosinusitis, which can spread to the orbits or intracranially via direct extension or through the valveless emissary veins. The organism can also enter via inhalation and then spread hematogenously. Isolated cerebral infection without sinusitis is highly correlated with intravenous drug use. In immunocompromised patients with sinusitis, inflammatory changes in the pre- and retromaxillary fat planes raise suspicion for angioinvasive fungal infections, which may present with or without osseous erosions. On MRI, the normally T2-hyperintense sinonasal mucosa may appear hypointense and lack contrast enhancement due to necrosis (the “black turbinate” sign) ( Fig. 3.6 ). Intracranially, angioinvasive hyphal forms such as Mucor or Aspergillus are likely to result in parenchymal disease ( Fig. 3.7 ). Intracranial infection can lead to encephalitis with varying degrees of enhancement and abscess formation. Areas of T1 hyperintensity and T2 hypointensity may be present, which have been attributed to iron, manganese, hemorrhage, and/or hemosiderin-laden macrophages.

Viral infections. Herpes simplex encephalitis (HSE) is the most common fatal sporadic encephalitis and is caused by the herpes simplex virus type 1. Although recurrent mucocutaneous viral infections are common in immunocompromised patients, the incidence of HSE is not increased in them, presumably because CNS damage results from both direct viral injury and indirect immune-mediated factors. The imaging hallmark of HSE is profound cortical edema affecting the medial temporal lobes, insula, cingulate gyrus, and inferior frontal lobes. Although the diagnosis may be suspected on CT, MRI with DWI is the imaging study of choice due to its higher sensitivity. In the acute stage, MRI shows restricted diffusion involving the limbic system that may be unilateral or bilateral and asymmetric. Patchy or gyral enhancement is common after several days, and hemorrhage is also frequent ( Fig. 3.8 ). Atypical presentations of HSE have been reported in immunocompromised patients, with widespread cortical, brainstem, or cerebellar involvement.

Varicella-zoster virus is another neurotropic herpesvirus that causes varicella (chickenpox) as a primary infection. The virus remains latent in neural tissues and may become reactivated later in life in the form of a vesicular rash (shingles) or with infection of the geniculate ganglion (Ramsay Hunt syndrome/herpes zoster oticus) or ophthalmic division of the trigeminal nerve (herpes zoster ophthalmicus) ( Figs. 3.9 and 3.10 ). Such infections are more common and severe in immunocompromised patients. Reactivation rarely results in meningoencephalitis, myelitis, or radiculitis. Patients can also develop a vasculitis involving small and large vessels, which may lead to infarction or hemorrhage ( Fig. 3.11 ). Unifocal large-vessel vasculitis usually affects the middle cerebral artery and appears to be more common in immunocompetent individuals. Vasculitis in immunocompromised patients is more commonly multifocal ( Fig. 3.12 ). MRI is the study of choice for evaluation of intracranial involvement and should include dedicated high-resolution sequences for evaluation of cranial neuropathies and ophthalmic involvement. On MRI, enhancement of the facial nerve and geniculate ganglion in Ramsay Hunt syndrome may be indistinguishable from Bell’s palsy, and therefore the presence of otic pain or vesicular eruption are important clues for the diagnosis. Compared with Bell’s palsy, patients with Ramsay Hunt syndrome are more likely to have more severe and persistent facial paralysis.

Cytomegalovirus is another member of the herpesvirus family that can result in latent infection. Encephalitis is a rare complication that develops in patients who are severely immunosuppressed, usually in the setting of AIDS. Imaging findings are nonspecific and can present in the form of encephalitis, ventriculitis, myelitis, and/or radiculitis ( Fig. 3.13 ).

The JC virus is a polyoma virus with a high rate of seropositivity among the general population, where it causes an asymptomatic latent infection. Reactivation may lead to PML, a devastating demyelinating disease that occurs almost exclusively in patients with profound cell-mediated immunosuppression. Most affected patients have HIV or hematologic malignancies or are being treated with immunosuppressive or immunomodulatory drugs, most notably natalizumab. PML initially affects the subcortical white matter in an asymmetric fashion and involves the U fibers. Extension to the corpus callosum and involvement of the parietooccipital white matter and middle cerebellar peduncles are common. MRI is the modality of choice, and a normal study argues strongly against the diagnosis. PML lesions have no significant mass effect and no significant contrast enhancement, although faint peripheral enhancement has been reported. On DWI, newer and larger lesions may show an advancing edge of restricted diffusion corresponding to cytotoxic edema ( Fig. 3.14 ).

Immune Reconstitution Inflammatory Syndrome (IRIS). Usually occurring in the setting of HIV, IRIS presents with paradoxical clinical deterioration after a patient is placed on ART and regains the capacity to mount an immune response. Onset after initiation of ART is variable and depends on underlying opportunistic infections, ranging from weeks to months. The inflammatory response may lead to worsening manifestations of a known or unknown infection. A wide number of organisms have been implicated in IRIS, including cytomegalovirus, cryptococcus, JC virus, and Mycobacterium tuberculosis . Incidence is inversely associated with CD4 count at the time of ART initiation, with counts typically below 100/mm ³ . However, IRIS has also been described in non-HIV patients with tuberculosis, where the CD4 count may be higher. Although usually self-limited, IRIS is associated with poor outcomes when there is involvement of the CNS. Its imaging hallmarks are edema, mass effect, and contrast enhancement at the site of previous infection, which are best visualized on MRI ( Fig. 3.15 ).

Tuberculosis. Tuberculosis saw a resurgence due to the AIDS pandemic, the emergence of multidrug- resistant mycobacteria, and socioeconomic factors. It continues to be one of the leading causes of death caused by a single infectious agent worldwide, and was only surpassed in 2020 as the top infectious cause of mortality by SARS-CoV-2. M. tuberculosis primarily infects the lungs and then progresses to other sites depending on the host’s immune status. CNS involvement occurs in 10% of non-HIV patients, and its risk is substantially higher in those with HIV, who are more likely to present with a disseminated infection. Most patients are severely immunosuppressed, with CD4 counts below 100/mm ³ . The main route of dissemination to the CNS is hematogenous, with development of meningeal or parameningeal granulomas that then burst to release infection into the subarachnoid spaces. Tuberculosis may cause meningitis (the dominant form), axial or extraaxial masses/granulomas, or disseminated infection. The classic imaging finding is a thick basal meningeal exudate with avid contrast enhancement, although such an appearance is less common in patients with HIV. This exudate leads to vascular and cranial nerve encasement resulting in vasculitis, infarction, and cranial neuropathies. Noncaseating tuberculomas appear as avidly contrast-enhancing solid masses that are typically hypointense on T2. Some undergo caseation with ring enhancement and others liquefy, resulting in a T2-hyperintense center that may be indistinguishable from a bacterial abscess. A miliary pattern with punctate enhancing lesions may be seen in patients with disseminated disease. Conglomerate ring-enhancing granulomas are a feature that is suggestive of tuberculosis ( Fig. 3.16 ). Hydrocephalus is common.

Nocardia. Nocardiosis is a rare infection caused by a gram-positive bacillus that primarily affects immunocompromised individuals. Infection in hospitalized patients most commonly involves the lungs followed by the CNS, and disseminated disease occurs in one-third of patients. Imaging findings are nonspecific, with abscesses being most common, followed by meningitis or a combination of both ( Fig. 3.17 ).

Relevant imaging findings for the diseases discussed above are summarized in Table 3.1 .