Central Nervous System

Neuroprotection can be defined as the mechanisms and procedures used to protect neuronal cells belonging to the central nervous system (CNS) against possible damage, apoptosis, loss of function or accelerated degeneration (Tucci & Bagetta, 2008).

From: Trends in Food Science & Technology, 2021

Neuro-Oncology

M. Sierra Del Rio, ... Hoang-Xuan Khe, in Blue Books of Neurology, 2010

Publisher Summary

Primary central nervous system (CNS) lymphomas (PCNSL) are extranodal malignant lymphomas arising within the brain, eyes, leptomeninges, or spinal cord in the absence of systemic lymphoma at the time of diagnosis. This chapter provides an overview of the PCNSL, pathology and pathogenesis, diagnosis, and treatment options of PCNSL. The chapter focuses on PCNSL in the immunocompetent population. The prognosis of PCNSL has considerably improved over the past few years, and a minority of patients can even hope to be cured. Appropriate treatment of PCNSL can lead to prolonged remission, frequently with remarkable patient recovery compatible with an active life; however, long-term survivors are at increased risk of developing severe delayed cognitive dysfunction that may seriously compromise their quality of life. Future treatment should improve the efficacy, while minimizing the risk of neurotoxicity, and new strategies will benefit not only from advances in the management of non-Hodgkin lymphomas (NHL) outside the CNS, but also from the better understanding of the specific PCNSL tumorigenesis.

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Central Nervous System Vasculitis

Ludovico D’Incerti, ... Gabriele Di Comite, in Neuroinflammation, 2011

Vasculitis Complicating Malignancies

CNS vasculitis related to malignancy has been most commonly reported in association with Hodgkin’s and non-Hodgkin’s lymphoma, typically with MRI findings consistent with small- and medium-vessel vasculitis and with histologic evidence of granulomatous angiitis. In such patients biopsy is recommended, since CNS infiltration by lymphoproliferative cells should be excluded to define the proper treatment. Treatment of the underlying disease can lead to resolution of the CNS manifestations, although recurrence of vasculitis in the absence of cancer relapse has been described [4,99–103].

Only anecdotally has CNS vasculitis been observed as a complication of solid tumors, including a biopsy-proven case in a patient with breast cancer [104]; one case, diagnosed by MRI and angiography, in a 12-year-old patient with Ewing sarcoma [105]; and one patient with pheochromocytoma with angiographic evidence of vasculitis [106]. In one case a myelodysplastic syndrome was complicated by CNS vasculitis mimicking PACNS [107].

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Gliomas

Brandon D. Liebelt, ... Amy B. Heimberger, in Handbook of Clinical Neurology, 2016

Central nervous system immunology

The CNS has traditionally been thought of as a space of immunologic privilege, limiting entry of immune cells and immune mediators. This belief stemmed from early experiments indicating increased growth of allograft carcinoma implanted in brain compared with its growth at subcutaneous sites in animal model systems (Medawar, 1948). The concept was based on several false assumptions, including: limited ability of immune cells and antibodies to penetrate the blood–brain barrier, lack of CNS lymphatics to drain antigen into peripheral lymph nodes, inability of resident CNS cells to sustain immune responses, low MHC levels within the CNS, and a relative deficiency of DCs within brain parenchyma. Yet, leukocytes are present in the CNS, even in the absence of infection or inflammation, although the composition of leukocytes there is not the same as is found in the peripheral blood (paucity of neutrophils and abundance of T cells in the CNS), indicating a selective barrier to entry. Leukocytes can gain access to the CNS through multiple routes, including from the blood to the cerebrospinal fluid (CSF) via the choroid plexus, from blood to the subarachnoid space, and from blood to the brain parenchyma (Ransohoff et al., 2003). The first route is probably physiologic in nature and follows the normal production of CSF along the choroid plexus. Extravasation into the subarachnoid space occurs at postcapillary venules in the Virchow–Robin space. Here, the leukocytes interact with competent APCs and function in the immune surveillance of the CNS. Additionally, antigens within the CNS have been shown to be delivered to lymphoid organs, particularly the deep cervical lymph nodes, which can then induce antigen-specific activation of naïve lymphocytes (Harling-Berg et al., 1999). Therefore, as immune surveillance actively occurs, antigens within the CNS can be presented in the lymphatic system (with leukocytes having several mechanisms to gain access to the CNS), and the immune system is a viable mechanism to combat intracranial neoplasms.

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Epitope Spreading in Autoimmune Diseases

Shivaprasad H. Venkatesha, ... Kamal D. Moudgil, in Infection and Autoimmunity (Second Edition), 2015

3.8 Site of Initiation of Epitope Spreading: Target Organ Versus the Periphery

The CNS has traditionally been viewed as being immune privileged. However, studies of PLP-induced R-EAE and TMEV-induced demyelination revealed that epitope spreading is initiated within the CNS.107 During the course of disease, naïve T cells enter the inflamed CNS and are activated there by local APCs to initiate epitope spreading. A recent study showing determinant spreading to CD8 + T cell epitopes in CD4 + T cell-induced EAE also emphasized the CNS as the site of epitope spreading.106 However, there also is evidence to suggest an alternative viewpoint emphasizing that the CNS-draining lymph nodes are important for the induction of immune response during relapses in chronic R-EAE.108 Surgical removal of these lymph nodes reduced the severity of relapses of EAE. This proposition is supported by the observation that myelin antigens are expressed in the lymph node, spleen, and thymus of SJL mice.109

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Dendritic cells in the central nervous system

Francesca Aloisi, ... Luciano Adorini, in Dendritic Cells (Second Edition), 2001

CONCLUSIONS

Research reviewed herein strongly implicates DCs in CNS immune surveillance and in the pathogenesis of CNS autoimmunity. While exclusion of DCs from the CNS parenchyma proper makes it less susceptible to potentially damaging cell-mediated immune responses, DC localization at anatomical sites that are constantly exposed to antigens leaving or entering the CNS ensures that this is not totally ignored by the immune system. It would be interesting to know whether CNS-associated DCs sense the specialized neural microenvironment and play a role in the maintenance of CNS immune privilege.

Many questions remain to be answered with respect to the contribution of DCs to CNS autoimmune responses. Although studies in the EAE model indicate that DCs have a role in the development and maintenance of CNS autoimmunity, direct evidence for DC involvement in human CNS autoimmune diseases, like MS, is still lacking. The role of different DC subsets in the regulation of CNS autoimmune responses and the precise phenotype of DCs recruited to the inflamed CNS also remain to be defined. Another important issue to clarify is the identity of the signals enabling trafficking and maturation of DCs within the CNS. Clarification of these issues will be essential to elucidate the contribution of DCs to CNS autoimmunity. This, in turn, will be instrumental to design therapeutic manipulation of DC function or blockade of DC migration to the CNS. It remains to be seen if DC targeting could be more effective than current immunomodulatory therapies in the treatment of CNS autoimmune disorders. Given the power of DCs in the regulation of the immune response, this may prove to be a worthwhile effort.

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Neurocutaneous Syndromes

Prashant Chittiboina, Russell R. Lonser, in Handbook of Clinical Neurology, 2015

General features

CNS hemangioblastomas are among the most common manifestations in VHL disease. Up to 72% of VHL patients may present with a CNS hemangioblastoma in the cerebellum (16–69%), brainstem (5–22%), spinal cord (13–53%), cauda equina (11%), or supratentorial (1–7%) locations (Filling-Katz et al., 1991; Poulsen et al., 2010; Binderup et al., 2013; Huntoon and Lonser, 2014; Lonser et al., 2014). Patients present with these lesions in their second or third decade. CNS hemangioblastomas are the most common (30–35%) and often the first manifestation of VHL (Maddock et al., 1996; Poulsen et al., 2010). Although benign, hemangioblastomas are a significant source of morbidity and mortality in VHL patients due to mass effect on CNS structures (Wanebo et al., 2003; Lonser et al., 2014).

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Neuroimaging Part II

Andre D. Furtado, ... Charles R. Fitz, in Handbook of Clinical Neurology, 2016

Abstract

Primary CNS tumors consist of a diverse group of neoplasms originating from various cell types in the CNS. Brain tumors are the most common solid malignancy in children under the age of 15 years and the second leading cause of cancer death after leukemia. The most common brain neoplasms in children differ consistently from those in older age groups. Pediatric brain tumors demonstrate distinct patterns of occurrence and biologic behavior according to sex, age, and race. This chapter highlights the imaging features of the most common tumors that affect the child’s CNS (brain and spinal cord).

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Autoimmune Neurology

Marinka Twilt, Susanne M. Benseler, in Handbook of Clinical Neurology, 2016

Differential diagnosis of adult PACNS

Similar to cPACNS, the differential diagnosis of adult PACNS includes secondary CNS vasculitis, nonvasculitic inflammatory brain disease, CNS vasculopathies, and other mimics of CNS vasculitis (Neel et al., 2012; Vera-Lastra et al., 2015). Secondary CNS vasculitis is similar across the age spectrum, although some presentations are seen more often or only in either childhood or adulthood (Table 16.2). Infections and other systemic underlying diseases are the most common causes for secondary CNS vasculitis (Neel et al., 2012; Vera-Lastra et al., 2015).

Table 16.2. Secondary central nervous system vasculitis in adults and children

AdultsChildren
Infections (Yankner et al., 1986; Calabrese, 1991; Ford-Jones et al., 1998; Nogueras et al., 2002; Rodriguez and Stone, 2006)
Bacterial infections
Streptococcus pneumoniae, Mycoplasma pneumoniae, Mycobacterium tuberculosis, Borrelia burgdorferi, Treponema pallidum, Salomonella typhi, other
Viral infections
Epstein–Barr virus, cytomegalovirus, varicella-zoster virus, parvovirus B19, enterovirus, hepatitis B virus, hepatitis C virus, West Nile virus, JC virus, human immunodeficiency virus
Fungus infections
Aspergillus, Coccidiodes, Candida albicans, Actinomyces spp., mycomycosis, Histoplasma capsulatum, Toxoplasma, Nocardia, Cryptococcus, other
Protozoal infections
Toxoplasma, Plasmodium, other
Systemic vasculitis (Nishino et al., 1993; Engel et al., 1995; von Scheven et al., 1998; Pomper et al., 1999; Nadeau, 2002; Mastorodemos et al., 2006; Moshous et al., 2007)
Takayasu arteritis
Polyarteritis nodosa
Antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis including granulomatosis with polyangiitis (GPA, formerly known as Wegener granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg–Strauss syndrome)
Behçet's disease
Giant cell arteritisKawasaki disease
Henoch–Schönlein purpura
Systemic rheumatic diseases (Alrawi et al., 1999; Aviv et al., 2006, 2007; Benseler et al., 2006; Kirton et al., 2006; Venkateswaran et al., 2008; Iannetti et al., 2012; Mandell et al., 2012; Abers et al., 2013)
Systemic lupus erythematosus, sarcoidosis, systemic scleroderma, others
Rheumatoid arthritis, Sjögren syndrome, othersJuvenile dermatomyositis, morphea, others
Systemic inflammatory disease/immune dysregulation (Akman-Demir et al., 2006; Moshous et al., 2007; Gupta and Weizman, 2010; Crow and Casanova, 2014; Garg et al., 2014; Navon Elkan et al., 2014; Zhou et al., 2014; De Felice et al., 2015)
Hemophagocytic lymphohistiocytosis (HLH), including primary HLH and secondary HLH/macrophage activation syndrome (MAS)
Inflammatory bowel disease
Autoinflammatory diseases, including cryopyrin-associated periodic syndromes (CAPS), familiar Mediterranean fever (FMF), others
Graft-versus-host disease, posttransplant lymphoproliferative disease (PTLD)
Cryoglobulinemia with vasculitisMonogenic immune dysregulations, including:

STING-associated vasculopathy with onset in infancy (SAVI)

Adenosince desaminase deficiency (DADA 2)

Aicardi–Goutière's syndrome (AGS)

Metabolic diseases (Mancuso et al., 2004, 2011; Winterthun et al., 2005; Tzoulis et al., 2010; Scalais et al., 2012)
Polymerase gamma (POLG) deficiency
McArdle disease glycogen storage disease
Vitamin B12 deficiency (Al Kawi et al., 2004)
Malignancies, including angioblastic T-cell lymphoma, others (Jellinger et al., 1979; Borenstein et al., 1988; Kleinschmidt-DeMasters et al., 1992)
Paraneoplastic vasculitis
Urticarial hypocomplementemic, malignancy-related vasculitis
Drug-induced vasculitis (Aoki et al., 2002)
Radiation-induced vasculitis (Aoki et al., 2002)

Although some features may be overlapping in patients, mimics of adult PACNS are divided into mimics of angiography-positive disease and mimics of angiography-negative, brain biopsy-positive disease (Table 16.4). In adult patients, the most important mimics are arteriosclerosis and vasospasm such as RCVS, which can be difficult to distinguish from PACNS (Hajj-Ali et al., 2002; Seror et al., 2006; Singhal et al., 2011; Neel et al., 2012). MRI with gadolinium wall enhancement could help to differentiate between angiography-positive disease and arteriosclerosis or RCVS. RCVS can lead to transient vessel stenoses and, although very rare in childhood, is seen more frequently in adults. RCVS is seen more in female patients and usually presents with thunderclap headaches. Other reversible vasoconstriction conditions, such as migraines, drug-induced or pregnancy-associated, should be considered. Overall, the differential diagnosis is wide and diverse and should be addressed with every patient who presents with suspected PACNS.

Table 16.4. Mimics of adult primary angiitis of the central nervous system (PACNS)

Mimics of angiography-positive PACNS
Noninflammatory vasculopathy (Pavlakis et al., 1984; Begelman and Olin, 2000; Hajj-Ali et al., 2002; Kirton et al., 2006; Rafay et al., 2006; Ibrahimi et al., 2010; Kraemer and Berlit, 2010; Testai and Gorelick, 2010a, b; Liu et al., 2011; Singhal et al., 2011; Kirton et al., 2013)
Intracranial atherosclerosis
Chronic hypertension vasculopathy
Intracranial dissection
Fibromuscular dysplasia
Moyamoya syndrome
Genetic cerebral vasculopathies
Connective tissue vasculopathies, including Marfan's syndrome, Ehlers–Danlos syndrome, ACTA2 mutations, Louis Dietz syndrome, transforming growth factor-beta receptor mutation
Mitochondrial diseases, including cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Fabry disease
Cerebral vasculopathy syndromes
Cogan syndrome (vasculopathy plus interstitial keratitis plus vestibular-auditory dysfunction)
Susac syndrome (noninflammatory vasculopathy resulting in retinopathy, hearing loss, and encephalopathy)
Vasculopathy syndromes
Kohlmeier–Degos disease (retinocerebral vasculopathy with cerebral leukodystrophy)
Hereditary endotheliopathy with retinopathy, nephropathy, and stroke
Sneddon syndrome (progressive, noninflammatory cerebral arteriopathy and livedo)
Conditions associated with cerebral vasospasms (Singhal et al., 2011; John et al., 2014)
Migraine
Reversible cerebral vasoconstriction syndrome, including postpartum angiopathy
Vasospasm secondary to hypertension
Other acquired vasospasms: drug-induced
Other conditions associated with vasculopathies
Hemoglobin diseases, including sickle cell disease, thalassemia
Thrombi or emboli:
Coagulopathies, including homocysteinuria
Antiphospholipid antibody syndrome
Infective and noninfective endocarditis
Myxoma and other cardiac tumors
Cholesterol atheroembolism
Radiation vasculopathy (Aoki et al., 2002)
Drug-induced vasculopathy
Malignancy-associated vasculopathies:
Angiotropic and intravascular lymphoproliferative disorders
Graft-versus-host disease
Intravascular lymphoma, gliomatosis cerebri
Mimics of angiography-negative, brain biopsy-positive small-vessel PACNS
Non-vasculitic inflammatory brain diseases
Acute disseminated encephalomyelitis (ADEM) (Mikaeloff et al., 2007; Alper et al., 2009)
Demyelinating diseases, including multiple sclerosis (MS), demyelinating optic neuritis, transverse myelitis (Banwell et al., 2007, 2011; Neuteboom et al., 2008; Alper and Wang, 2009; Thomas et al., 2011)
Progressive multifocal leukoencephalopathy
Antibody-mediated inflammatory brain diseases (Cross and Golumbek, 2003; Wingerchuk and Weinshenker, 2003; Wiljeto et al., 2006; Banwell et al., 2008; Dalmau et al., 2008; Florance et al., 2009; Shulman, 2009; de Oliveira and Pelajo, 2010; Graus et al., 2010; Luca et al., 2011; Titulaer et al., 2013)
Neuromyelitis optica (NMO)
Anti-NMDAR encephalitis
Other limbic encephalitis (anti-LGI, AMP, GAD, other)
Suspected antibody-mediated inflammatory brain diseases (PANDAS, Hashimoto encephalitis, celiac disease-associated inflammatory brain diseases)
Granulomatous inflammatory brain diseases (neurosarcoid) (Lie, 1992; Rose et al., 2009)
Infectious encephalitis
Posterior reversible encephalopathy syndrome (PRES)
Malignancies

NMDAR, N-methyl-d-aspartate receptor; PANDAS, pediatric autoinflammatory neuropsychiatric disorder associated with streptococcal infections.

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OTHER SECONDARY HEADACHE DISORDERS

Todd J. Schwedt, David W. Dodick, in Neurology and Clinical Neuroscience, 2007

Primary Angiitis of the Central Nervous System and Reversible Cerebral Vasoconstriction Syndrome

PACNS is a vasculitis that is limited to the central nervous system in its distribution. Patients usually present with a headache that is subacute or slowly progressive in onset, severe, and focal or diffuse.48,49 The headache may be accompanied by nausea and vomiting. However, it is usually associated with other neurological manifestations, including hemiparesis, mental impairment, dysphasia, or seizures.50 Symptoms of PACNS may fluctuate in their severity but eventually progress over time. This often leads to delayed diagnosis; as many as 40% of cases are diagnosed after symptoms have been present for more than 3 months.50 Systemic symptoms, such as fever and weight loss, occur much less commonly than with systemic vasculitides. The diagnosis of PACNS can be made through a combination of CSF analysis, angiography, or central nervous system biopsy. CSF analysis often reveals significantly elevated protein levels and white blood cell count in patients with pathologically confirmed PACNS.51 The classic finding on cerebral angiography is a pattern of alternating areas of segmental narrowing and ectasia, producing a beaded or sausage-like appearance. Pathological specimens reveal fibrinoid necrosis and infiltration of vessel walls by lymphocytes, multinucleated giant cells, and/or histiocytes.52 PACNS tends to be an aggressive disease and is uniformly fatal without treatment. Response to cytotoxic/immunosuppressive therapy is variable; remissions are possible in some patients.

RCVS is a unifying diagnosis for a group of disorders characterized by reversible segmental cerebral vasospasm and more benign outcomes than those seen with PACNS. This includes thunderclap headache with vasospasm, benign angiopathy of the central nervous system, migrainous vasospasm or crash migraine, Call-Fleming syndrome, postpartum angiopathy, and drug-induced vasospasm.53–55 Patients with RCVS present with the acute onset of sudden and severe headache, consistent with thunderclap headache. Evaluation reveals normal or near-normal CSF findings and reversible cerebral segmental vasospasm involving arteries of the circle of Willis. The diagnostic criteria for RCVS are (1) a thunderclap headache, (2) evidence of vasospasm of one or more arteries of the circle of Willis that reverses by 12 weeks after onset, and (3) normal or near-normal CSF studies (Table 60-5). Patients may have a history of migraine, may be in the postpartum period, or have had exposure to certain drugs, including ergotamines, triptans, selective serotonin reuptake inhibitors, pseudoephedrine, cocaine, amphetamines, methylenedioxymethamphetamine (ecstasy), or bromocriptine.56–87 Patients with RCVS may differ in regard to the presence and/or severity of neurological deficits, imaging abnormalities, and circumstances at the time of symptom onset. Patients may present with thunderclap headache in isolation or in combination with changes in cognition or consciousness, motor deficits, sensory deficits, seizures, visual disturbances, ataxia, speech abnormalities, nausea, and/or vomiting.

Because the angiographic appearance of segmental cerebral vasospasm in RCVS is identical to that seen in PACNS, these two entities must be differentiated, to avoid the unnecessary use of long-term immunosuppressants and cytotoxic agents in patients with RCVS. The clinical characteristic that best differentiates RCVS from PACNS is the acuity of headache onset and other clinical features. In contrast to patients with RCVS, who have a rapid onset of symptoms, patients with PACNS usually have a slowly progressive onset of disease and may accumulate new manifestations over weeks to months. Laboratory tests are also helpful in differentiating these two entities. Results of CSF analysis are markedly abnormal in approximately 80% of patients with PACNS but are generally normal in patients with RCVS.88 Cerebral imaging may appear normal in RCVS and usually appears abnormal in PACNS. In PACNS, MRI typically shows multifocal lesions secondary to ischemia or infarction distributed in the middle cerebral artery territory. Normal MRI, when diffusion and perfusion sequences are included, is uncommon in patients with symptomatic PACNS.89–92 In contrast, a greater proportion of patients with RCVS have normal brain MRI. However, abnormalities may be seen and are often consistent with posterior reversible leukoencephalopathy or watershed infarctions in the distribution of vasospastic blood vessels.93,94 RCVS cannot be differentiated from PACNS by the initial vascular imaging study, inasmuch as both show segmental vasospasm. However, even in the absence of any specific treatment, patients with RCVS have significant reversal of vasospasm within 4 weeks of symptom onset and complete normalization within several months.

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HIV-1 Tat toxin

Shilpa Buch, Honghong Yao, in Reproductive and Developmental Toxicology, 2011

Concluding Remarks And Future Directions

CNS disease remains a serious complication in individuals infected with HIV-1. The early viral protein, HIV Tat, has been shown to be a critical determinant for both viral replication and survival. However, in the infected host release of Tat from the infected cells can have serious consequences, as it exerts potent toxicity on various cell types in the brain. In the CNS it can activate monocytes, astrocytes and microglia, which, in turn, leads to a “cytokine/chemokine storm” in the CNS. HIV-1 Tat not only exerts direct toxicity on the neurons, but can also indirectly lead to neuronal apoptosis, via the mediators released from other neighboring cells. These complex cascades of events could be self-propelling, thereby perpetuating a continuum of inflammatory responses in the brain of HIV-1-infected individuals. These are important issues even in the current era of antiretrovirals, since most of the therapeutic drugs do not cross the BBB. HIV Tat can also disrupt the BBB integrity, allowing for increased numbers of inflammatory cells into the CNS. Furthermore, Tat can also cooperate with various drugs of abuse to potentiate toxicity thereby amplifying untoward inflammatory responses in the CNS. HIV Tat thus acts at multiple steps within the CNS to exacerbate disease pathogenesis, and understanding its contributions at various stages of the disease process is crucial for developing strategies that could interfere with disease induction and/or progression.

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