Immunologically Mediated Disorders

During the past years, an increased awareness of autoimmune and paraneoplastic inflammatory disorders that lead to cognitive and behavioral changes has been developed. Clinicians should be aware of some clinical clues that may help to identify patients with these potentially treatable dementias: subacute or rapid progressive presentation with a fluctuating course; varied and, often, multifocal neurological manifestations besides neuropsychiatric symptoms (e.g., epilepsy, ataxia, parkinsonism, tremor, myoclonus, brainstem signs, myelopathy, peripheral nervous system disorder); personal or family history of autoimmunity or cancer and cancer risk factor; serologic evidence of coexisting autoimmunity (organ-specific or non-organ- specific autoantibodies) and/or cellular inflammation; presence of a neural-specific autoantibody or an underlying cancer; inflammatory changes in CSF; brain MRI and/or EEG abnormalities; and improvement after a course of immunotherapy and/ or treatment of the underlying tumor, in the case of paraneoplastic disease .

Limbic and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis are two of the most common neuropsychiatric syndromes associated with antineuronal antibodies, caused either by paraneoplastic conditions produced by a known or occult cancer or by an autoimmune process with or without an underlying tumor. Limbic encephalitis is, typically, characterized by subacute confusion, short-term memory loss, seizures and psychiatric symptoms ranging from mood disorders (depression, irritability, anxiety, and obsessive-compulsive behavior), personality changes, sleep disturbances, hallucinations, and psychosis. In general, patients with autoimmune limbic encephalitis (i.e., autoantibodies targeting extracellular epitopes or synaptic proteins as LGI1, GABAbR, AMPAR, mGluR5, Caspr2, GAD65, and GlyR[1]) have a more favorable response to treatment and prognosis than patients with paraneoplastic limbic encephalitis (i.e., antibodies against intracellular antigens as Hu/ ANNA1, Ri/ANNA2, Ma2/Ta, CV2/CRMP5, and amphiphysin[2]). Treatment is directed at treatment of the underlying cancer and immunosuppression.

NMDAR encephalitis is most frequently found in younger women, sometimes associated with an underlying ovarian teratoma. Patients, often, have a prodrome of headache, fever, and gastrointestinal and/or respiratory symptoms, followed by psychiatric manifestations (anxiety, insomnia, fearfulness, agitation, social withdrawal, hallucinations, delusions, disinhibition, mania, catatonia), memory loss, language disturbances, movement disorders (oro-lingual-facial dyskinesia, chorea, dystonia, oculogyric crisis, rigidity, opisthotonic posture), seizures, and status epilepticus, eventually evolving to decreased level of consciousness, autonomic instability, and hypoventilation [71]. Serum or CSF antibodies of immunoglobulin type G against

NR1 subunit of NMDAR are diagnostic. Inflammatory changes in CSF are common, and brain MRI may show nonspecific increased T2/FLAIR hyperintensity in the internal temporal region and cerebral/cerebellar cortex. Treatment consists in tumor resection and immunosuppression [72].

Hashimoto encephalopathy, also known as steroid-responsive encephalopathy associated with evidence of thyroid autoimmunity (SREAT), refers to a triad of encephalopathy, thyroid autoimmunity with high levels of antithyroperoxidase (TPO) and/or antithyroglobulin (TG) antibodies, and clinical improvement with corticosteroids. Two different types of presentation have been seen: relapsing/ remitting course with acute or subacute stroke-like episodes, resulting in focal neurological deficits and variable cognitive dysfunction, and impaired consciousness and chronic subtype with a diffuse progressive pattern, characterized by gradual cognitive dysfunction and behavioral symptoms, resembling a neurodegenerative dementia. The most common manifestations in Hashimoto encephalopathy are cognitive impairment, neuropsychiatric symptoms, seizures, tremor, myoclonus, and impaired consciousness. The pathophysiologic mechanism is a matter of controversy, whether it represents a syndrome itself or stands for an epiphenomenon associated to an underlying autoimmune disorder, once patients often have other coexistent autoimmune diseases. Antithyroid antibodies are the hallmark feature of Hashimoto encephalopathy; however, they can be found in up to 10 % of the general population, and, therefore, they should only be considered clinically relevant when a combination of encephalopathy and high antibody levels is seen in a patient in whom other more common infectious, metabolic, and toxic causes have been ruled out. Laboratory, in the majority of cases, finds a euthyroid status, and electrophysiological and radiographic features are nonspecific. Diagnosis should lead to prompt corticosteroid therapy, generally, with a dramatic response [73].

Cerebral vasculitis is a heterogeneous group of disorders involving the CNS vasculature, pathologically characterized by inflammation and necrosis of the blood vessel wall. Primary vasculitis of the CNS, also known as primary angiitis of the CNS (PACNS), is a rare vascular inflammatory disease limited to the CNS, with predilection for small-medium-sized vessels supplying the brain parenchyma, spinal cord, and leptomeninges. Its broad clinical features include multifocal or diffuse CNS symptoms that develop gradually over weeks with a fluctuating-remitting pattern or stepwise progressive course, comprising headaches, meningeal signs, encephalopathy, psychiatric manifestations, stroke, seizures, cranial nerve palsies, myelopathy, and rapid progressive dementia. Similarly, CNS involvement can be found among patients with secondary cerebral vasculitis, which embraces different conditions: primary systemic vasculitis, connective tissue disorders, other inflammatory systemic diseases, cerebral amyloid angiopathy-related inflammation, infectious diseases, drug abuse vasculitis, and paraneoplastic vasculitis (Table 6.2) [74-78]. A complete workup should be performed in order to exclude such secondary causes of vasculitis and vasculopathy of the CNS. In PACNS, routine laboratory tests are frequently within the normal range, but may reveal anemia of chronic disease, leukocytosis, and elevation of inflammatory markers (ESR) and C-reactive

Table 6.2 Laboratory evaluation of secondary vasculitis of the central nervous system [74-78]

Primary systemic vasculitis

ANCA-mediated small vessel-sized vasculitis

Granulomatosis with polyangiitisa (Wegener granulomatosis)

c-ANCA/PR3 antibodies

Eosinophilic granulomatosis with polyangiitisa (Churg-Strauss syndrome)

pANCA/MPO and c-ANCA/PR3 antibodies

Microscopic polyangiitis

pANCA/MPO antibodies

Immune complexes small vessel-sized vasculitisb

Cryoglobulinemic vasculitis


Hepatitis C, HIV, lymphoproliferative diseases, and plasma cell dyscrasias

Medium vessel-sized vasculitisc

Polyarteritis nodosaa

Hepatitis B, solid tumors, and hematological neoplasm

Large vessel-sized vasculitis

Giant cell arteritisa

Erythrocyte sedimentation rate

Takayasu’s arteritisd

Anti-endothelial antibodies

Connective tissue disorders associated with vasculitis

Systemic lupus erythematosusa,e

ANA, anti-dsDNA, anti-SM antibodies

Antiphospholipid antibodies [false-positive VDRL, anticardiolipin antibodies, anti-p2-GP1, and lupus anticoagulants]

Behget diseasea

HLA-B51 and HLA-B27

Sjogren syndromea

ANA, anti-Ro/SS-A, anti-LA/SSB antibodies Rheumatoid factor

Rheumatoid arteritis

Rheumatoid factor

Relapsing polychondritis


Systemic sclerosis

Anti-SCL70, anti-centromere antibodies

CREST syndrome

Anti-centromere antibodies


Creatinine kinase

Mixed connective tissue diseasea

ANA, antiphospholipid, anti-RNP antibodies

Inflammatory systemic disorders associated with vasculitis


ACE, calcium

Susac syndromea

Anti-endothelial antibodies

Gluten sensitivity

Antigliadins, anti-tTG, anti-EMA, anti-DGP antibodies


Cogan syndrome


Bowel inflammatory diseases

Anti-ASCA in Crohn’s disease

pANCA/MPO antibodies in ulcerative colitis

Thromboangiitis obliterans (Buerger’s disease)

HLA-A9, HLA-A54, and HLA-B5


Table 6.2 (continued)

Primary systemic vasculitis

Cerebral amyloid angiopathy-related inflammation

Infectious disorders associated with vasculitis

Infective endocarditisa

Blood cultures

Bacterial meningitis


Viral disorders [hepatitis B and C, HIV1, CMV, EBV, VZV1, parvovirus B19, mumps, California encephalitis, Coxsackie

CSF analysis

Spirochetal disordersa [syphilis, Lyme disease]

Tissue biopsies

Bacterial disorders [Bartonella spp., Trichinella spp., Mycoplasma pneumoniae, beta-hemolytic Streptococcus]

Mycobacterial disordersa [M. tuberculosis]

Rickettsial disorders [Rocky Mountain spotted fever, typhus]

Parasitic disorders [neurocysticercosis]

Fungal disorders [aspergillosis, candidiasis, coccidioidomycosis, mucormycosis]

Free-living amoebae

Drug-, chemical-, and radiation-induced vasculitis

Paraneoplastic vasculitis

Hematologic malignancies

Electrophoresis, immunofixation, and quantitative evaluation of immunoglobulins

Plasma cell dyscrasias

LDH, beta-2 microglobulin, and calcium

Solid tumors

Laboratory tests in suspected vasculitis

Complete blood count

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

Complement levels: C3, C4, and CH50

Chemistry panel, including liver and renal tests, electrolytes with calcium, CPK, LDH, and ACE


Autoantibodies: ANA, anti-dsDNA, anti-SSA/Ro, anti-SSB/La, pANCA/MPO, c-ANCA/PR3, anti-SM, anti-SCL70, rheumatoid factor, anti-endothelial

Coagulation tests, including anticardiolipin and anti-p2-GP1 antibodies and lupus anticoagulants

Serum and urine electrophoresis, immunofixation, and quantitative evaluation of immunoglobulins

Serology for infectious disease: VDRL and TPHA, Borrelia burgdorferi antibodies (ELISA, immunoblot), HIV, hepatitis B and C

Blood cultures

CSF cell differentiation, cultures, serology, and PCR tests

Urine examination

Drug screening


Table 6.2 (continued)

Primary systemic vasculitis

Tissue biopsies according to the clinical suspicion (e.g., biopsy of the temporal artery, muscle and nerve, meningeal and cerebral cortex, skin, small bowel, lip/minor salivary gland, lymph nodes)

ACE angiotensin-converting enzyme, anti-j)2-GP1 anti-beta-2 glycoprotein I, ANA antinuclear antibody, anti-ASCA anti-S. cerevisiae antibody, anti-dsDNA anti-double-stranded DNA, c-ANCA/ PR3 circulating antineutrophil cytoplasmic antibody/proteinase-3, pANCA/MPO perinuclear antineutrophil cytoplasmic antibody/myeloperoxidase, anti-DGP anti-deaminated gliadin peptide, anti-EMA anti-endomysial antibodies, anti-RNP anti-U1 ribonucleoprotein, anti-SS anti-Sjogren syndrome-related antigen, anti-SM anti-Smith, anti-tTG anti-tissue transglutaminase, CMV cytomegalovirus, CPK creatine phosphokinase, CREST syndrome calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, CSF cerebrospinal fluid, EBV Epstein- Barr virus, ELISA enzyme-linked immunosorbent assay, HIV human immunodeficiency virus, HLA human leukocyte antigen, LDH lactate dehydrogenase, PCR polymerase chain reaction, TPHA Treponema pallidum hemagglutination, VDRL venereal disease research laboratory, VZV varicella-zoster virus

aVasculitis most frequently involving the central nervous system bHenoch-Schonlein purpura or IgA vasculitis in children

cKawasaki disease may occasionally involve the central nervous system in children

dCentral nervous system complications in Takayasu’s arteritis are mainly due to involvement of

extracranial vessels and not directly due to cerebral vasculitis

eCerebral vasculopathy, other than cerebral vasculitis, can be present in systemic lupus erythematous, such as antiphospholipid antibody-related thrombosis, cardiac emboli, and thrombotic thrombocytopenic purpura protein (CRP). CSF analysis is useful to exclude infection and malignancy and, in PACNS, typically demonstrates mild inflammatory changes, including mild lym- phomonocytic pleocytosis or protein elevation. Normal brain MRI almost excludes intracranial vasculitis; however, there are no pathognomonic MRI findings: many ischemic lesions of different ages; single or multiple territorial infarcts and hemorrhages; nonspecific T2 hyperintense lesions involving the cortex, basal ganglia, and white matter; widespread micro-bleeds; leukoencephalopathy; and gadolinium enhancement of the meninges. Diagnosis may be suggested by conventional angiography with a typical vasculitic pattern with multifocal narrowing and vessel occlusions, but it could be entirely normal or unspecific. Furthermore similar images can be present in other diseases, either secondary causes of vasculitis or vasculitis- mimics. The gold standard for PACNS diagnosis is a brain biopsy with surrounding leptomeninges, demonstrating vasculitis pathology (granulomatous, lymphocytic, necrotizing, or mixed patterns); however, since lesions are segmental, a normal biopsy does not completely exclude the diagnosis. Recommended treatment for PACNS consists on immunosuppression therapy, but the prognosis is usually poor. Treatment and prognosis of secondary cerebral vasculitis and vasculopathies depend mostly on the cause [74-78].

Several systemic inflammatory disorders can be responsible for encephalopathy manifestations, rapidly progressive dementia, mood disorder, and/or psychosis,

Table 6.3 Non-neuropsychiatric features in inflammatory systemic diseases involving the central nervous system

Neurological features

Systemic features

Systemic lupus erythematosus

Cerebrovascular disorder (stroke and cerebral venous thrombosis)

Malar rash, discoid rash, photosensitivity


Mouth and nose ulcers


Nonerosive arthritis


Serositis (pericarditis and pleuritis)


Proteinuria or urine sediment

Demyelinating syndromes

Hemolytic anemia, leukopenia, or thrombocytopenia

Peripheral nervous system involvement: polyneuropathy, AIDP, mononeuritis multiplex, cranial neuropathy, autonomic neuropathy

Antiphospholipid syndrome


Vascular thrombosis (arterial and/or venous)

Cerebrovascular disorder (stroke and cerebral venous thrombosis)

Pregnancy morbidity: unexplained spontaneous abortions, fetus deaths, premature births


Livedo reticularis


Ocular ischemia


Association of systemic lupus erythematosus and other autoimmune disorders

Peripheral neuropathy and AIDP


Orthostatic hypotension

Sjogren syndrome


Sicca syndrome

Multifocal CNS involvement relapsing- remitting course (^multiple sclerosis)

Rheumatoid arthritis association

Neuromyelitis optic association

Association of systemic lupus erythematosus

Aseptic meningitis



Peripheral nervous system involvement: painful sensory neuropathy, sensory ataxic neuronopathy, multiple mononeuropathy, polyradiculopathy, trigeminal sensory neuropathy, cranial neuropathy, autonomic neuropathy

Behcet disease


Oral and genital ulcers


Uveitis, retinal vasculitis


Positive pathergy test, erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules


Table 6.3 (continued)

Neurological features

Systemic features



Cerebral venous thrombosis

Gastrointestinal symptoms

Intracranial hypertension

Arterial aneurysms and intracranial arteritis

Peripheral nervous system involvement: polyneuropathy, multiple mononeuropathy

Gluten sensitivity


Dermatitis herpetiformis


Aphthous stomatitis




Gastrointestinal symptoms



Malabsorption syndrome



Hilar adenopathy, diffuse infiltrates, upper lobe fibrosis

Cerebellar ataxia

Granulomatous angiitis of the CNS

Lupus pernio, annular lesion, erythema nodosum

Acute aseptic or chronic meningitis

Uveitis, optic neuritis, lacrimal gland swelling

Meningeal mass lesions



Hypercalcemia and nephrolithiasis


Cardiomyopathy, intraventricular conduction, and nodal defect

Neuroendocrine dysfunction




Cranial mononeuropathy

Renal failure

Peripheral nervous system involvement: multiple or single mononeuropathy, polyneuropathy, polyradiculopathy, autonomic neuropathy

Anemia, leukopenia, and thrombocytopenia



Bone and joints

Susac syndrome


Branch retinal artery occlusions

Typical brain MRI abnormalities: T2/FLAIR “spoke” lesion and “snowballs” in the central portion of the corpus callosum; T1 central callosal “holes”; DWI “string of pearls” in internal capsule; leptomeningeal enhancement

Sensorineural hearing loss

diffusion-weighted imaging, FLAIR fluid attenuation inversion recovery, MRI magnetic resonance imaging including diverse entities as systemic lupus erythematosus, antiphospholipid syndrome, Sjogren syndrome, Behget disease, gluten sensitivity, sarcoidosis, and Susac syndrome. The involvement of CNS in these pathologies could have different mechanisms: antibody or cellular attack directed against brain parenchyma; antibody- mediated thrombosis/noninflammatory vasculopathy; immune complex-mediated inflammatory vasculitis; and coagulopathy. In some disorders, other neurological noncognitive or psychiatric features can be present, and also systemic manifestations may be salient, facilitating the correct identification of the entity (Table 6.3). Workup for these systemic disorders includes inflammatory markers, serology autoimmunity studies (complement tests and autoantibodies), as well as laboratory and complementary tests to confirm specific organ involvement (Table 6.2). In the context of neuropsychiatric symptoms, brain MRI and CSF are strictly important to identify suggestive patterns or nonspecific changes and to exclude other diagnoses. Reversibility of cognitive impairment in inflammatory conditions, on directed- treatment and/or immunosuppression, is highly variable [72].

Patients with multiple sclerosis can often develop some degree of cognitive impairment during their lifetime, even from the early clinical stages of the disease. A relapsing-remitting course of cognitive changes has been described, characterized by subacute cognitive decline in an acute relapse and subsequent improvement during remission [79], but, most commonly, a neurocognitive progressive disability is appreciated. The cognitive domains most frequently affected are working memory, attention, processing speed, recent memory, executive functions, and visuospa- tial functions [80, 81]. Medications, especially sedatives and anticholinergic drugs, and comorbid fatigue, depression, anxiety, and emotional lability, may further interfere with cognitive tasks. Treatment of cognitive impairment is challenging and generally based on immunomodulatory therapy for the underlying disease, treatment of symptomatic manifestations, as well as appropriate management of the very common comorbid psychiatric disease.

  • [1] LGI1, leucine-rich, glioma-inactivated 1; GABAbR, gamma-aminobutyric acid B receptor;AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; mGluR5, metabotropic glutamate receptor 5; Caspr2, contactin-associated protein-like 2; GAD65, glutamic aciddecarboxylase; GlyR, glycine receptor.
  • [2] ANNA1, antineuronal nuclear antibodies 1; ANNA2, antineuronal nuclear antibodies 2; CRMP5,collapsin response mediator protein 5.
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