The herpesvirus family consists of a large group of DNA viruses, where humans are the sole reservoirs for them. This family include HSV-1 and HSV-2, varicella zoster virus (VZV), CMV, Epstein–Barr virus (EBV) and herpes virus type 6 (HHV-6) and type 7 (HHV-7).

HIV is a human retrovirus that causes AIDS. There are two subtypes, HIV-1 and HIV-2. Although HIV-1 is present all over the world, HIV-2 is found most frequently in West Africa. HIV has infected approximately 75 million people, causing an estimated 36 million deaths since the disease outbreak in 1981. It is estimated that 35.3 million people are infected with HIV, and almost 1.6 million people died from AIDS in 2012. Although only approximately 10% of the world’s population lives in sub-Saharan Africa, this area corresponds to almost 70% of the world’s HIV population, 25 million people, and 1.2 million AIDS-related deaths. At the end of 2012, the HIV epidemic in the United States had infected around 1.2 million people. The
introduction of highly active antiretroviral therapy (HAART) decreased the overall incidence of AIDS and substantially increased survival after AIDS diagnosis. However, disparities remain among racial/ethnic minority populations.

HIV is a neurotrophic organism that enters the CNS soon after exposure (17). HIV causes neuronal injury leading to cognitive impairment. The neurologic manifestations of HIV infection, in the absence of superimposed opportunistic infection or neoplasm, include encephalopathy, myelopathy, peripheral neuropathy, and myopathy.

Pathologically, HIV brain infection causes significant injury. Inflammatory changes habitually occur in the subcortical regions, including the deep white matter and gray matter such as basal ganglia and thalamus. Neurologic dysfunctions are not directly related to neuron infection. A combination of factors, including HIV infection and activation of immunocompetent cells and toxins, may contribute to the pathogenesis of neurologic dysfunction (17). There is an increase in the number of multinucleated giant cells, and macrophages—the cellular target of HIV infection—seem to be related to the progressive encephalopathy seen in AIDS (Fig. 14.14). Polymorphic microglia and, less frequently, astrocytes are also infected. Astrocyte axonal damage has been associated with high viral loads. Myelin pallor and tissue rarefaction is related to the presence of multinucleated giant cells located primarily in the white matter (18).

AIDS dementia complex (ADC), the most common neurologic manifestation in AIDS patients, was previously referred to as subacute encephalitis or subacute encephalopathy. ADC is related to direct viral invasion of neurons (19). Clinical presentation includes progressive dementia with deterioration of mental function associated with movement disorders and/or behavioral dysfunction (34). HIV infection leads to various degrees of neurologic abnormalities that may progress to cognitive impairment and dementia (20).

Clinicopathologic correlation in patients with ADC suggests that the primary pathologic substrate is subacute encephalitis with multinucleated giant cells rather than microglial nodules. Electron microscopy reveals retrovirus particles within these multinucleated giant cells, and their presence strongly correlates with ADC. The multinucleated giant cells may be present within the cortex, basal ganglia, and/or white matter. Early difficulties with memory and concentration are often followed by apparent apathy and social withdrawal and may be mistaken for symptoms of depression. Headache is also a frequent complaint, and seizures are seen in approximately 10% of cases. Diffuse atrophy is usually present. Gross examination often reveals only atrophy.

Initially, lesions are present in the white matter; with disease progression, they can extend to the basal ganglia and cortex. In some patients, the white matter lesions predominate, whereas in others, the gray matter is more severely affected. Lesions may also be located in the brainstem, cerebellum, and spinal cord.

HIV may also directly result in acute encephalitis and acute or chronic meningitis. The viral meningitis typically presents with fever, headache, and meningeal signs, and usually remits spontaneously but can recur. Neuroimaging is usually negative. Clinical symptoms suggest the diagnosis of HIV encephalitis before the evidence of any imaging abnormality. CT is not as sensitive as MR in detecting changes related to HIV infection. In some cases, although MR has shown diffuse white matter disease and HIV has been cultured from brain tissue, the CT has been negative. White matter lesions are infrequently detected by CT in patients with HIV encephalopathy. CT may demonstrate nonspecific diffuse brain atrophy, with no other abnormalities in most subacute encephalitis cases.

Although MRI is more sensitive than CT in depicting brain alterations in HIV-positive individuals, conventional MR sequences are not necessarily able to demonstrate any abnormality in the earliest stages of infection to determine the real extent of damage (17). Cortical atrophy is the most frequent MR finding and is usually the only early modification. A central predominance brain atrophy is noted. Atrophy progresses over time, and some authors correlate this progression with the decline of cognitive abilities. T2-weighted images and FLAIR images reveal hyperintense lesions without mass effect involving much of the periventricular white matter and centrum semiovale that correspond to demyelination and vacuolation (Fig. 14.14). Lesions do not enhance. Lesions may vary from scattered, isolated, unilateral foci to confluent bilateral involvement and may be symmetric or asymmetric (Fig. 14.15). The extent of disease roughly parallels the clinical neurologic deterioration.

The differential diagnosis between HIV encephalitis and progressive multifocal leukoencephalopathy (PML) can be a challenge in clinical and radiologic practices (see subsequent section on PML), but MRI findings form the basis of defining the specific diagnosis in these patients. Although the neuroradiologist
should be able to distinguish these entities in the great majority of cases, variability in size, extent, and distribution of lesions in both HIV-related demyelination and PML, especially early in the course of disease, can preclude a definitive diagnosis based on the MR appearance alone. In general, HIV encephalitis has a pattern of diffuse centrum semiovale and periventricular white matter hyperintensity, in contrast to the unifocal or asymmetric multifocal pattern typically produced by PML (Fig. 14.16). The demyelination lesions of HIV encephalitis tend to be more symmetric and central than those of PML. Although both entities appear hyperintense on T2-weighted images, the lesions of HIV demyelination are usually unapparent on T1-weighted images, whereas those of PML are often clearly hypointense and well-demarcated on T1-weighted images. In PML, lesions often involve the posterior fossa and tend to be located in the posterior portion of the brain. The frontal lobes are the most common sites of involvement in HIV encephalitis. Although neither entity typically has significant contrast enhancement as a major component of its MR findings, it is certainly not uncommon for an edge of enhancement or occasionally tiny foci of enhancement to be seen in PML (Fig. 14.16). Finally, these two entities have different clinical manifestations that are extremely helpful in clinical correlations. HIV encephalitis often manifests as a global encephalopathy, whereas PML is usually associated with a focal neurologic deficit. Given all of these factors, a final confounding issue is that this patient population can simultaneously harbor more than one brain pathology.

Some evidence supports the idea that the CNS is a reservoir for HIV. A viral load increase is associated with a decline in neurocognitive functions. Early in the course of infection, HIV enters the CNS (21). Among asymptomatic HIV-seropositive patients, brain atrophy and multifocal signal abnormalities on T2-weighted images have been shown. MR abnormalities have been reported in approximately 50% of patients with an AIDS-related complex and around 70% of patients with AIDS. These abnormalities included sulcal and ventricular enlargement and
patchy areas of hyperintensity on T2-weighted images without mass effect. Over time, in parallel with the clinical progression of cognitive deterioration, white matter lesions become more diffuse, homogeneous, and confluent, and cerebral atrophy increases (22).

In a follow-up study, MR tests were performed in asymptomatic HIV-seropositive patients and then repeated 2 to 4 years later. Eighty percent of these tests were found to be normal and remain normal. Twenty percent had minor abnormalities that were static and stable. Serial examinations of patients with mild neurologic symptoms revealed that 50% of MR scans were mildly abnormal but remained stable. The MR findings of minor abnormalities in asymptomatic HIV-seropositive patients may not be clinically significant because they apparently remain stable.

HAART is a treatment regimen that causes suppression of viral replication, resulting in a decreased viral load (often to undetectable levels). This is essential for neurologic integrity because high CSF viral loads clearly correlate with cognitive impairment in patients with HIV-related dementia. Other effects of this treatment include increased CD4 counts, as well as decreased morbidity and increased survival (17).

Drug treatments with zidovudine and HAART (21) have shown reductions in CSF viral loads, reductions in white matter HIV-related lesions on MRI, and improvements in cognitive function. A neuroimaging marker for HIV-associated neurofunctional changes in the brain is essential for detecting early modifications in mental status. Thus, these techniques could be useful in measuring response to HAART (21).

Proton MR spectroscopy is a valuable tool in the assessment of patients with HIV infection. This MR method is able to depict brain metabolite changes in asymptomatic HIV-infected patients with no abnormalities on conventional MRI sequences. Thus, it seems that proton MR spectroscopy may reveal cerebral abnormalities before they are apparent on standard imaging and holds a promise of early diagnosis of biochemical alterations in HIV-infected patients.

A reduction in the levels of NAA (Fig. 14.17), a neuronal functional marker, is evident in the early onset of infection, even in asymptomatic individuals. The decline is greater in symptomatic than asymptomatic patients. The reduced N-acetylaspartate/creatine (NAA/Cr) and N-acetylaspartate/choline (NAA/Cho) ratios support a theory of neuronal loss and/or dysfunction as a contributing factor to ADC and seem to indicate subtle biochemical modifications that correlate with the clinical neurologic findings but were completely unapparent on conventional imaging studies. However, some patient may have abnormal imaging and a normal spectrum. Thus, the information provided by the two techniques appears to be complementary (Fig. 14.18). An eventual drop in NAA/Cr ratio appears to correlate with the progressive neurologic deterioration in patients with more advanced disease. Whole-brain NAA measurement has also demonstrated a diffuse reduction both in symptomatic and asymptomatic patients before abnormalities in parenchymal brain signal intensity.

Some authors have found that although NAA/Cr and NAA/Cho ratios are reduced in patients with moderate to severe ADC, patients with early ADC or no dementia have MR spectra similar to those of control subjects (23). NAA levels may improve in some patients with ADC in response to treatment.

Choline is a cell membrane metabolite marker that may represent increased cell membrane turnover and/or membrane disruption with cellular damage. MRS may reveal an increase in choline compounds earlier than the NAA reduction in patients with cerebral HIV infection (24). Thus, an elevated choline level appears to be a useful marker for early cerebral injury secondary to HIV and is high before the onset of clinical dementia (24). The increased choline is present in both early and late stages of HIV infection. Choline levels are not directly related to clinical status or CD4 counts.

mI is a marker for neuroglial cell activation. Atrophy and gliosis may lead to an increase of mI as a result of neuroglial cell proliferation with replacement of damaged neurons. A high mI/Cr ratio has been seen in patients with atrophy and diffuse white matter disease on MR, as well as in HIV patients without dementia. Some investigators have found a less prominent elevation in mI/Cr in patients with ADC. Although mI seems to be elevated in the early course of cerebral HIV infection, it may be less prominent with advancing dementia (25). In summary, MRS analysis in early stages of HIV dementia seems to be associated with an increase in both choline and mI levels.

On MRS examination after use of HAART, a normalization of the Cho/Cr ratio in the basal ganglia and a reduction of the mI/Cr ratio in the basal ganglia and frontal lobe white matter were noted. This decline correlated well with changes in CD4 counts and improvement in ADC stage. The authors suggested that mI might be a very good in vivo marker for monitoring brain injury in patients with HIV infection. The early stages of HIV dementia may be treatable and possibly reversible.

Diffusion imaging can show white matter abnormalities even though no structural changes are seen on conventional MRI. This finding may be consistent with early MRS metabolite abnormalities in the white matter. Among HIV patients with dementia, white matter hyperintensity on T2-weighted imaging and FLAIR imaging is frequently observed. A significant increase in diffusivity and reduction in fractional anisotropy (FA) values may be related to an increase in viral load (21,26). These changes have been noted prior to the onset of cognitive impairment. Whole-brain diffusion tensor imaging (DTI) correlates with the severity of dementia. Thus, DWI and DTI sequences may be important for the early detection and initiation of ADC treatment. The disruption of white matter fiber microstructure integrity may provide an early indication of the potential for HIV-associated dementia (Fig. 14.19) (18). Although these findings seem promising, a previous report did not demonstrate significant usefulness of DTI in depicting early diffusion abnormalities of normal-appearing white matter in patients with HIV infection (17).

PML is a rare opportunistic subacute progressive demyelinating disorder caused by JC polyomavirus in immunocompromised patients. The histopathologic hallmark of PML is demyelination with enlarged oligodendroglial nuclei and bizarre astrocytes (32).

The JC virus is widespread, with antibodies found in 50% to 70% of the human population by the age of 65 years. The infection does not produce overt illness and remains dormant in the kidneys, tonsils, possibly B lymphocytes, and bone marrow unless there is reactivation due to immunodeficiency (33) or immune suppression. AIDS and other immunodeficiency conditions, including lymphoproliferative and myeloproliferative disorders, chronic granulomatous diseases, sarcoidosis, and use of immunosuppressive drugs for organ transplantation, rheumatologic conditions and mAb therapy, like natalizumab, are associated with PML. Although PML is associated to severe depletion of cellular immunity, recently reports have associated this condition with less overt immunodeficiency, such as cirrhosis, renal failure, psoriasis, dermatomyositis, and even pregnancy (34). The prevalence of PML has increased greatly since the beginning of the AIDS epidemic. It appears to have a stronger association with AIDS because the incidence of PML increases concomitantly with the rise in AIDS. In approximately 0.7% to 11% of patients who have HIV develop PML during the course of the illness, and recently, up to 85% of PML cases have been attributable to AIDS. Since the introduction of HAART, the incidence of PML has shown a tendency to diminish. Clinical and imaging-documented improvements, associated with longer survival, have also been reported.

Clinically, PML is characterized by progressive neurologic deficits leading to death (without therapy) in approximately 2.5 to 4 months of the onset of symptoms (32). PML causes death in 90% of patients within 1 year after diagnosis. Only a small number of cases have a more benign clinical course. The most common symptoms of PML are hemiparesis, visual impairment, and altered mentation, whereas patients with lesions of the posterior fossa exhibit ataxia, dysarthria, and dysmetria. Spinal cord involvement is rare. Approximately 20% of patients develop seizures in addition to the focal neurologic symptoms. Other clinical features include memory loss, visual deficit (frequently homonymous hemianopsia), personality changes, cognitive and speech disturbances, altered mental status, and motor and/or sensory abnormalities with a progressive neurologic decline. Less frequent signs and symptoms include vertigo, seizures, headache, and aphasia.

Brain biopsy is the most definitive way to establish a specific diagnosis of PML, in which the triad of demyelination, giant atypical astrocytes, and oligodendrocytes with intranuclear inclusion bodies is found (Figs. 14.16 and 14.24). New imaging tools and CSF studies are emerging as potential mechanisms to replace brain biopsies in the diagnosis of PML (33). The
need for a less invasive method has been recognized. However, most CSF analyses using PCR testing are normal (35). Sensitivity and specificity for PML detection in the CSF via PCR are about 92%. A positive CSF PCR and a high JC virus DNA load are associated with diminished survival.

PML appears as multifocal hypodense white matter lesions involving the subcortical or periventricular regions without causing significant mass effect and usually without enhancement on imaging. CT, however, is frequently negative, especially in early stages of disease, so it is virtually never used to image these patients unless MRI is unavailable. Patchy enhancement at the periphery of lesions is seen in less than 10% of cases. As in any modality, serial scans indicate progressive disease.

MR demonstrates far greater sensitivity than CT in the imaging of PML for defining both the extent and the number of lesions and is always the procedure of choice in imaging any patient with suspected PML. PML lesions on MR images are hypointense on T1-weighted images and hyperintense on T2-weighted images involving the periventricular and/or subcortical white matter, producing a “scalloped” appearance (Figs. 14.25 to 14.27). Initially, lesions may be small, but they usually progress to larger areas of involvement (Figs. 14.28 and 14.29). Lesions usually have a bilateral, multifocal, and asymmetric distribution pattern, and may occur in any location in the white matter, most often in the parietal lobe, followed by the frontal lobe (32) (Fig. 14.27). Mass effect is infrequent and mostly minimum. PML lesions are estimated to enhance in about 10% of cases on MR. When enhancement is present, it is faint and typically at the periphery of lesions In some cases, there may be microcysts at the center of an active lesion on T2-weighted image (Fig. 14.20) (36). It is believed to signify a more intense inflammatory reaction and may be a predictive factor for prolonged survival (17); however, it has also been reported in aggressive cases associated with certain pharmacologic treatments of multiple sclerosis (MS) (Fig. 14.30) (37). Occasionally, mild mass effect is present (35). It has been suggested that mass effect, increased atrophy, confluence of lesions, and increased hypointensity on follow-up T1-weighted MR studies can be regarded as indicators of a poor prognosis in untreated AIDS patients with PML. However, only the mass effect was related to predicting the risk of death in patients with PML. PML may also appear to affect the deep gray structures due to involvement of small myelinated fibers that course through the basal ganglia and adjacent structures (Fig. 14.26). The thalamus is the most common affected region, followed by the basal ganglia. Usually the gray matter lesion is associated with white matter involvement.

PML commonly affects the posterior fossa (Fig. 14.16). Approximately one-third of PML cases have some involvement of the posterior fossa. There are often synchronous with supratentorial lesions, although PML may be limited to the infratentorial structures in about 10% of cases. Typically the lesions involve the middle cerebellar peduncle and adjacent pons and cerebellum.

In AIDS patients, PML lesions do not typically resemble HIV encephalopathy causing demyelination, but they are occasionally difficult to distinguish on imaging (see the earlier section on HIV encephalopathy). As stated earlier in more detail, PML is more often discrete, multifocal, and asymmetric, with scalloping and a greater predilection for the subcortical white matter. HIV encephalitis is more often ill-defined, diffuse, symmetric, and periventricular in location. Clinical correlation is
important as well, as mentioned earlier, because HIV encephalitis most often presents with global cognitive disturbances and dementia, whereas PML presents with a focal motor or sensory deficit.

Some new MR sequences may play a role in detecting subtle abnormalities in PML patients, such as MT, DWI, DTI, and MRS (33). In the research literature, MT MRI seems to be more sensitive for depicting demyelination processes than conventional imaging in group studies. Thus, it may be possible indirectly to verify the integrity of the myelin sheaths. It may also be feasible, according to a previous report, to distinguish the destructive demyelination of PML from the edematous changes related to HIV encephalopathy. Quantitative MT methodology, however, has not found its way into clinical imaging protocols on individual patients at the time of this writing.

MRS has also been used to characterize and differentiate PML from other CNS HIV-related processes (Fig. 14.31). NAA reductions and creatine peaks have been seen (38). There is also an increase in choline, excess lipids, and lactate, as well as an occasional increase in mI. These changes seem to
parallel some of the pathologic features of PML. Decreased NAA shows an association with neuronal loss, cell membrane and myelin breakdown cause an increase in Cho, and a rise in glial activity leads to increased mI (38). A marked elevation of mI/Cr levels in the early stage of the disease may be related to a favorable outcome. The extent of the inflammatory reaction is directly related to the high mI peak elevation. Early in the course of PML, elevations in Cho and mI are seen, secondary to the inflammatory reaction and myelin destruction. In more advanced disease, neuronal compromise leads to a progressive decrease in NAA and an eventual decrease in all metabolites. The mild elevations of lactate and lipids likely result from macrophages and the breakdown of cell membrane and myelin (38).

DWI can be used to monitor the degree of demyelination (39). The appearance of PML lesions on DWI varies according to the disease stage. DWI may show increased apparent diffusion coefficient values in the central area of the lesion, surrounded by a small rim of decreased diffusibility. This may represent a heterogeneous pathologic process in which the central area corresponds to complete tissue injury with necrosis and reduced cellularity. The peripheral region consists of active tissue injury (Figs. 14.32 and 14.33). The presence of multiple small areas of decreased diffusion throughout the entire cerebral white matter may indicate a merging of multiple areas of tissue injury to form large confluent lesions (39). DTI shows a reduction of FA values when apparent diffusion coefficient values are normal and no abnormality is demonstrated on T2-weighted images (40) (Fig. 14.34). The reduction of FA values follows the pathologic sequence of PML events. In an early phase, these reduced FA values represent an injury of myelin sheaths. It is followed by secondary diffuse cellular loss, leading to increased apparent diffusion coefficient values. DTI and DWI may be of great use in the management of PML patients for guiding and monitoring the treatment (39,40).

Besides brain biopsy, diagnosis of PML can be established by MRI or demonstration of JCV DNA by PCR of the CSF (36). However, it has become frequent to have a negative CSF exam in AIDS patients with PML. Recently, the diagnostic criteria classify PML as “definite PML” or “presumptive PML.” “Definite PML” is considered when there are consistent clinical and imaging findings associated with a positive PCR or defined in the brain biopsy. In the “presumptive PML,” clinical and imaging findings are not associated with a positive JCV DNA in the CSF.

No established treatment has been approved for PML. Recently, various drugs have been used that have shown some improvement in patient survival. The widespread introduction of HAART has led to a sharp decline in both morbidity and mortality associated with opportunistic infections. PML patients treated with HAART display reduced CSF detection of the JC virus, increased CSF production of antibodies to JCV-VP-1, increased survival, improved neurologic status, and improved or stabilized MR findings after 12 months of treatment. Survival improvement after HAART has been observed in some PML patients but not in all.

With restoration of immunity with HAART, there may be an abrupt change in the clinical behavior and histopathologic and imaging manifestations of PML in some patients (36). This altered presentation has a profound clinical significance and needs to be differentiated from the classic presentation. Three new CNS manifestations of JC virus infection have been recently recognized and described: meningitis (JCM), encephalopathy (JCE), and granular cell neuronopathy (JVCGCN).

There is a characteristically involvement of the cerebellum in the JVCGCN, which infects only cerebellar granule cell neurons, sparing the oligodendrocytes. Clinical symptoms are restricted to the cerebellar involvement, including ataxia and dysarthria. Some reports demonstrated JCV infections causing meningoencephalitis in immunocompetent patients (36). More recently, an encephalopathic form of CNS infection by JCV was described.

PML is typically characterized by a distinct lack of inflammatory change. Rarely, reactivation of the JCV and development of PML can be associated with a marked inflammatory reaction (36). A paradoxical worsening of inflammatory changes is noted in the first few months after the onset of HAART (33). A marked enhancement may be seen soon after the beginning of HAART, corresponding to an increased inflammatory response, attributable to the immune reconstitutive effect, associated with lesions associated with mass effect and vasogenic edema (17). In patients with PML, the risk of death is decreased by as much as 60% if the treatment regimen includes a protease inhibitor. However, HAART does not prevent progression of PML in all cases and may not be effective in all patients who develop PML while receiving HAART. Approximately half of the patients who have AIDS with PML do not experience benefit from HAART (Table 14.1) (32).

More recently, patients with MS that underwent to monoclonal antibody therapy using natalizumab developed PML (Fig. 14.28) (37). One possible explanation is a natalizumab-triggered reactivation of latent JC virus.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is extremely rare in developed countries. In the United States, approximately 46,000 persons are infected with HTLV-1. However, HTLV-1 is endemic in developing countries. HTLV-1 can cause tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and adult T-cell leukemia/lymphoma. HAM and TSP are characterized by a slowly progressive disabling disorder, with paraparesis, mild sensory disturbance, and urinary incontinence. Other conditions, such as isolated peripheral polyneuropathy, myopathy, arthropathy, and uveitis, have been associated with HTLV-1. Apparently, HTLV-1 causes disease in a minority of the infected population, with prevalence of neurologic involvement less than 3%.

Although clinically similar to certain forms of MS, TSP is a distinct entity based on epidemiologic studies and serologic tests. The white matter lesions of TSP/HAM are in some aspects similar to those observed in patients with MS or in HIV-infected people. Chronic perivascular inflammatory changes occur diffusively in the CNS, leading to multifocal leukoencephalopathy.

Autopsy studies have shown that both HAM and TSP involve primarily the spinal cord, especially the thoracic cord, where inflammatory changes, demyelination, and axonal loss may be seen. A more widespread chronic meningoencephalomyelitis is also present, with inflammatory changes involving the meninges, brainstem, and both supratentorial and infratentorial white matter. Thickening of the media and adventitia of blood vessels in the subarachnoid space, the spinal cord, and in the brain suggests vasculitis as well. Although HTLV-1 has been isolated from CSF lymphocytes of a patient with HAM, it is uncertain whether the neuropathologic changes are due to HTLV-1-infected lymphocytes or direct neurotropism of the retrovirus.

MRI reveals punctate and nodular hyperintense white matter lesions on T2-weighted imaging and FLAIR imaging in the periventricular and subcortical white matter in more than 60% of HTLV-1-infected patients (41) (Fig. 14.35). The white matter lesions do not enhance or cause mass effect. Lesions are most often discrete but may be confluent. The appearance is nonspecific and must be differentiated from other white matter lesions such as MS, Lyme disease, HIV-related demyelination, ischemia, and vasculitis. Serial studies reveal an increase in the number of these white matter lesions in affected patients. The spinal cord can also be involved, presenting foci or multifoci hyperintense lesions.

Prion diseases, also known as transmissible spongiform encephalopathy, comprise a group of very rare progressive neurodegenerative disorders that affect both humans and nonhuman animals. These diseases are recognized on pathology by their characteristic spongiform brain changes with neuronal loss and a lack of inflammatory response and are clinically known for long incubation periods (32).

The transmissible agent of these disorders is believed to an abnormal form of human prion protein. Normal-occurring human prion protein is coded by a gene on the short arm of chromosome 20. The normal prion protein, called cellular prion protein (PrP^c) is rapidly degraded by proteolysis, whereas the abnormal form, termed scrapie prion protein (PrP^sc), is not. The agent induces abnormal folding of normal cellular prion proteins in the brain, leading to accumulation of PrP^sc in the brain in plaques. Brain damage and the characteristic signs and symptoms of the disease ensue. Prion diseases are usually rapidly progressive and always fatal. A number of different specific mutations of the PrP have been identified in familial cases (Table 14.2).

Human prion disease had traditionally been classified into three clinical syndromes: kuru, Creutzfeldt–Jakob disease (CJD), and Gerstmann–Straüssler–Scheinker (GSS) disease. However, with recent advances in understanding the etiology of prion disease, a more appropriate way to consider CJD is to divide it into familial (inherited), sporadic, and acquired subtypes. The sporadic forms are divided into sporadic Creutzfeldt–Jakob disease (sCJD) and sporadic fatal insomnia. The familial prion diseases
consist of familial CJD, fatal familial insomnias, and GSS disease. The acquired diseases are kuru, iatrogenic CJD, and new variant CJD (vCJD) (42).

Kuru is a neurodegenerative disorder characterized primarily by cerebellar ataxia. Kuru was quite common in the first half of the twentieth century in members of the Fore linguistic group living in the eastern highlands of Papua New Guinea. Transmission was from ritual cannibalism. Because this practice was outlawed in the 1950s, kuru is now almost nonexistent. Kuru is clinically characterized by progressive cerebellar ataxia, and, in contrast to CJD, dementia is not a prominent feature.

GSS originally was described as an inherited condition characterized primarily by cerebellar ataxia, with dementia occurring late in the disease. In contrast to CJD, the clinical course in GSS is more prolonged, with a mean duration of 5 years and clinical onset in the 20s to 30s.