**3. PET in diagnosis of autoimmune neurological disorders**

#### **3.1. Multiple sclerosis**

MS is an immune-mediated inflammatory, demyelinating disease of the CNS [22]. The etiology is not known, but it is supposed to involve a combination of genetic predisposition and certain triggers (e.g., various viral infections, low vitamin D levels) that cause recurrent immune attacks [28]. MS is supposed to be associated with certain genetic loci, which are known to influence the regulation of the immune system and higher susceptibility to this autoimmune disease [12]. Strong relationship exists with class II alleles (HLA-DR2, HLA-DR15), T-cell receptor gene, genes synthesizing immunoglobulins, tumor necrosis factor-α (TNF-α), and myelin basic protein (MBP).

MS is an inflammatory disease of the CNS characterized by the dissemination lesions of demyelination, called plaques, in the brain and spinal cord [32]. The main pathological changes include the degeneration of axons, astrocytes-induced gliosis, and sclerosis [22]. The stepwise lesion formation enlists the activation of myelin-reactive T cells in the periphery, breakdown of the BBB, penetration of activated inflammatory cells (lymphocytes and macrophages), and B-cell activation (generation of antibodies to MBP). Evidence exist that MS plaques are associated with expression of high levels of Interleukin (IL)-12 and B7-1, stimulating the release of proinflammatory cytokines [28]. Functionally-decreased T-lymphocytes with regulatory role (Tregs), microglia, dendritic cells, natural killer (NK) cells, and nonimmune (endothelial) cells are also involved in the mechanisms of CNS inflammation.

MS is diagnosed on the basis of clinical findings, brain magnetic resonance imaging (MRI), and cerebrospinal fluid examination (CSF) [31, 32]. Additionally, (18F)-FDG PET scans reveal the localization and distribution of cerebral hypometabolism in relation to demyelinating lesions in the white matter and their remote influence over the glucose metabolism of cortex, basal ganglia, and cerebellum [5, 10]. This method is also useful in MS patients with cognitive dysfunction for investigation of global and regional cerebral glucose metabolism in compar‐ ison to MRI findings [35]. According to Bakshi R et al. [3] and Derache N et al. [9], (18F)- FDG PET scans have clinical application as a marker for assessment of disease activity and response to immunotherapy. Although, cerebral imaging studies show variable results [6, 15, 16, 27], our (18F)-FDG PET findings in MS patients with certain cognitive impairment reveal areas of hypometabolism, corresponding to the white matter lesions and brain atrophy (Clinical case 1).

**Clinical case 1**. A 44-year-old male with relapsing-remitting MS and cognitive impairment. Neuroimaging findings (Fig. 1, 2, and 3).

#### **3.2. Autoimmune cerebellar ataxia**

Late-onset progressive cerebellar disorders can result from various pathologic processes, including malformations, degenerative and vascular disorders, infections, neoplasms, paraneoplastic syndromes, toxic/metabolic disorders, and demyelinating disease [1]. It is known that the immune system plays an important role in the development of paraneoplastic Positron Emission Tomography in Autoimmune Disorders of the Central Nervous System http://dx.doi.org/10.5772/61171 45

**Figure 1.** MRI shows MS lesions expressed in the left cerebral hemisphere.

**3. PET in diagnosis of autoimmune neurological disorders**

cells are also involved in the mechanisms of CNS inflammation.

MS is an immune-mediated inflammatory, demyelinating disease of the CNS [22]. The etiology is not known, but it is supposed to involve a combination of genetic predisposition and certain triggers (e.g., various viral infections, low vitamin D levels) that cause recurrent immune attacks [28]. MS is supposed to be associated with certain genetic loci, which are known to influence the regulation of the immune system and higher susceptibility to this autoimmune disease [12]. Strong relationship exists with class II alleles (HLA-DR2, HLA-DR15), T-cell receptor gene, genes synthesizing immunoglobulins, tumor necrosis factor-α (TNF-α), and

MS is an inflammatory disease of the CNS characterized by the dissemination lesions of demyelination, called plaques, in the brain and spinal cord [32]. The main pathological changes include the degeneration of axons, astrocytes-induced gliosis, and sclerosis [22]. The stepwise lesion formation enlists the activation of myelin-reactive T cells in the periphery, breakdown of the BBB, penetration of activated inflammatory cells (lymphocytes and macrophages), and B-cell activation (generation of antibodies to MBP). Evidence exist that MS plaques are associated with expression of high levels of Interleukin (IL)-12 and B7-1, stimulating the release of proinflammatory cytokines [28]. Functionally-decreased T-lymphocytes with regulatory role (Tregs), microglia, dendritic cells, natural killer (NK) cells, and nonimmune (endothelial)

MS is diagnosed on the basis of clinical findings, brain magnetic resonance imaging (MRI), and cerebrospinal fluid examination (CSF) [31, 32]. Additionally, (18F)-FDG PET scans reveal the localization and distribution of cerebral hypometabolism in relation to demyelinating lesions in the white matter and their remote influence over the glucose metabolism of cortex, basal ganglia, and cerebellum [5, 10]. This method is also useful in MS patients with cognitive dysfunction for investigation of global and regional cerebral glucose metabolism in compar‐ ison to MRI findings [35]. According to Bakshi R et al. [3] and Derache N et al. [9], (18F)- FDG PET scans have clinical application as a marker for assessment of disease activity and response to immunotherapy. Although, cerebral imaging studies show variable results [6, 15, 16, 27], our (18F)-FDG PET findings in MS patients with certain cognitive impairment reveal areas of hypometabolism, corresponding to the white matter lesions and brain atrophy

**Clinical case 1**. A 44-year-old male with relapsing-remitting MS and cognitive impairment.

Late-onset progressive cerebellar disorders can result from various pathologic processes, including malformations, degenerative and vascular disorders, infections, neoplasms, paraneoplastic syndromes, toxic/metabolic disorders, and demyelinating disease [1]. It is known that the immune system plays an important role in the development of paraneoplastic

**3.1. Multiple sclerosis**

44 Immunopathology and Immunomodulation

myelin basic protein (MBP).

(Clinical case 1).

Neuroimaging findings (Fig. 1, 2, and 3).

**3.2. Autoimmune cerebellar ataxia**

**Figure 2.** (18F)-FDG PET reveals areas of hypometabolism related to MS lesions and brain atrophy expressed mainly in the left cerebral hemisphere.

and nonparaneoplastic types of cerebellar ataxia [38]. Clinical data suggest that immunemediated cerebellar ataxia may be caused by autoantibodies to various cerebellar targets [39]. Anti-voltage-gated calcium channel (VGCC), -Yo (Purkinje cell antigen), -ANNA-3, -Ri, -Hu, -Ma, -PCA-2, and -mGluR antibodies are found in patients with paraneoplastic cerebellar ataxia. In contrast, nonparaneoplastic ataxia is associated with anti-GAD, -gliadin, and thyroid antibodies. Cross-reaction between tumor and cerebellar antigens is thought to be an underlying mechanism of autoimmune paraneoplastic ataxia [33]. The detection of circulating

**Figure 3.** (18F)-FDG PET reveals areas of hypometabolism related to MS lesions and brain atrophy expressed mainly in the left cerebral hemisphere.

autoantibodies in patients with nonparaneoplastic cerebellar ataxia supports the notion that the immune system is also involved in the pathogenesis of these sporadic cases.

The diagnosis is usually suggested by the presence of atrophy of the cerebellum and brainstem on computed tomography scans (CT) and magnetic resonance imaging (MRI) [1, 38]. In addition, PET is useful in the investigation of patients with acute or chronic ataxias [33]. Functional neuroimaging with (18F)-FDG improves the detection of etiology and understand‐ ing of underlying pathophysiologic mechanisms in patients with late-onset cerebellar ataxia. Certain investigations reveal a reduction in absolute values of regional cerebral glucose metabolism in the cerebellar hemispheres and vermis, as well as in the brainstem or dentate nuclei [24, 25]. We report similar (18F)-FDG PET observations on our patient with anti-Yo antibody-positive late-onset cerebellar ataxia, associated with two different types of tumors (Clinical case 2). In contrast, Wang P et al. [41] show various patterns of cerebral glucose metabolism in patients with ataxia.

**Clinical case 2.** A 49-year-old female with skin melanoma and ovarian cyst in accordance with autoimmune (paraneoplastic) cerebellar ataxia. (18F)-FDG PET findings (Fig. 4 and 5).

#### **3.3. Autoimmune limbic encephalitis**

Limbic encephalitis is a severe, neuropsychiatric disorder that affects the limbic system, which is responsible for the basic autonomic functions [14]. Based on the etiology, it is divided into two clinical forms: viral and autoimmune. The inflammation in the latter is caused by the autoimmune process that involves medial temporal lobes. Autoimmune limbic encephalitis (ALE) may be either paraneoplastic, which is associated with a large number of cancers (lung, breast, testicular, thymoma, Hodgkin lymphoma) or idiopatic (non-paraneoplastic) [18, 20]. ALE can be associated with the presence of autoantibodies to two groups of antigens: intra‐ cellular neuronal and cell-surface [39]. The first group includes Hu, Mu2, Ri, glutamic acid Positron Emission Tomography in Autoimmune Disorders of the Central Nervous System http://dx.doi.org/10.5772/61171 47

**Figure 4.** (18)F-FDG PET reveals strongly reduced metabolic activity in the cerebellum.

autoantibodies in patients with nonparaneoplastic cerebellar ataxia supports the notion that

**Figure 3.** (18F)-FDG PET reveals areas of hypometabolism related to MS lesions and brain atrophy expressed mainly in

The diagnosis is usually suggested by the presence of atrophy of the cerebellum and brainstem on computed tomography scans (CT) and magnetic resonance imaging (MRI) [1, 38]. In addition, PET is useful in the investigation of patients with acute or chronic ataxias [33]. Functional neuroimaging with (18F)-FDG improves the detection of etiology and understand‐ ing of underlying pathophysiologic mechanisms in patients with late-onset cerebellar ataxia. Certain investigations reveal a reduction in absolute values of regional cerebral glucose metabolism in the cerebellar hemispheres and vermis, as well as in the brainstem or dentate nuclei [24, 25]. We report similar (18F)-FDG PET observations on our patient with anti-Yo antibody-positive late-onset cerebellar ataxia, associated with two different types of tumors (Clinical case 2). In contrast, Wang P et al. [41] show various patterns of cerebral glucose

**Clinical case 2.** A 49-year-old female with skin melanoma and ovarian cyst in accordance with autoimmune (paraneoplastic) cerebellar ataxia. (18F)-FDG PET findings (Fig. 4 and 5).

Limbic encephalitis is a severe, neuropsychiatric disorder that affects the limbic system, which is responsible for the basic autonomic functions [14]. Based on the etiology, it is divided into two clinical forms: viral and autoimmune. The inflammation in the latter is caused by the autoimmune process that involves medial temporal lobes. Autoimmune limbic encephalitis (ALE) may be either paraneoplastic, which is associated with a large number of cancers (lung, breast, testicular, thymoma, Hodgkin lymphoma) or idiopatic (non-paraneoplastic) [18, 20]. ALE can be associated with the presence of autoantibodies to two groups of antigens: intra‐ cellular neuronal and cell-surface [39]. The first group includes Hu, Mu2, Ri, glutamic acid

the immune system is also involved in the pathogenesis of these sporadic cases.

metabolism in patients with ataxia.

the left cerebral hemisphere.

46 Immunopathology and Immunomodulation

**3.3. Autoimmune limbic encephalitis**

**Figure 5.** (18)F-FDG PET reveals strongly reduced metabolic activity in the cerebellum.

dexcarboxylase (GAD), amphiphysin, and collapsing responce-madiator protein 5. Voltagegated potassium channels (VGKC), N-methyl-d-aspartate receptor (NMDAR), α-amino-3 hydroxy-5-methyl-4-isoxazoleproprionic acid (AMRAR) belong to the latter antigen group.

The diagnosis of ALE is based upon clinical features (memory loss, temporal lobe epilepsy, and psychiatric syndrome), MRI, electroencephalography (EEG), and cerebrospinal fluid analysis [14]. Cerebral (18F)-FDG PET studies describe different scan patterns in patients with ALE [4, 8]. According to Fisher R et al. [11], one is specific to the disease and presents a combination of pronounced occipital hypometabolism and hypermetabolism in the temporal and orbitofrontal cortex. We describe the similar findings in one patient with idiopathic ALE (Clinical case 3). The other pattern closely resembles a diffuse neurodegenerative disease. Rey C et al. [30] report three cases with non-paraneoplastic limbic encephalitis characterized by (18F)-FDG PET bilateral striatal hypermetabolism, in contrast to diffused hypometabolism in the rest of the brain.

**Clinical case 3.** A 35-year-young male with idiopathic autoimmune limbic encephalitis. Neuroimaging findings (Fig. 6 and 7).

**Figure 6.** Coronal magnetic resonance-fluid attenuated inversion recovery (MRI-FLAIR) shows bilateral increased sig‐ nal of hypothalamus and amygdala.

**Figure 7.** The (18F)-FDG PET scan reveals the nonhomogeneous distribution of cortical metabolic activity with discreet reduction in the left parietal region; hypermetabolism in both medial temporal lobes to hippocampi.

#### **4. Summary**

C et al. [30] report three cases with non-paraneoplastic limbic encephalitis characterized by (18F)-FDG PET bilateral striatal hypermetabolism, in contrast to diffused hypometabolism in

**Clinical case 3.** A 35-year-young male with idiopathic autoimmune limbic encephalitis.

**Figure 6.** Coronal magnetic resonance-fluid attenuated inversion recovery (MRI-FLAIR) shows bilateral increased sig‐

**Figure 7.** The (18F)-FDG PET scan reveals the nonhomogeneous distribution of cortical metabolic activity with discreet

reduction in the left parietal region; hypermetabolism in both medial temporal lobes to hippocampi.

the rest of the brain.

48 Immunopathology and Immunomodulation

Neuroimaging findings (Fig. 6 and 7).

nal of hypothalamus and amygdala.

Although there are recent advances in molecular and cellular neurobiology, achievements of neurogenetics, and application of modern anatomical and functional neuroimaging techni‐ ques, the human brain is still an "enigma" and several immune-mediated inflammatory and neurodegenerative diseases of the CNS remain diagnosed late and unsuccessfully treated. Accordingly, a future research in basic neuroimmunology and innate mechanisms of autoim‐ munity is necessary to provide more precise immunodiagnostic assays and modern thera‐ peutic approaches in patients with neurological autoimmune diseases. Furthermore, the development of new radiology methods and specific radiotracer biomarkers for the needs of neuroinflammation and degeneration imaging is another serious precondition to guarantee the early detection and adequate treatment of immune-mediated damages of the CNS. Respectively, existing clinical data support the notion that PET scanning improves the medical diagnosis, differentiation, monitoring, and prognosis of certain debilitating autoimmune diseases that affect the brain and spinal cord tissue.
