Tcell AIE - symptoms
o The classical presentation of encephalitis consists of a subacute (days to a few weeks) progressive decrease in the level of consciousness, often with fluctuations, and altered cognition.
o Memory, especially retention of new information, may be impaired early in the clinical course. Patients may progress to coma
- can be paraneoplastic with additional symptoms
Tcell AIE - patho mechs
- T-cell mediated autoimmune encephalitis (AE) is often characterized by antibodies (Abs) against intracellular antigens.
- Abs against intracellular antigens do not have known pathogenic effects, but can serve as biomarkers for AE.
- Instead, neurons present intracellular antigens via MHC I molecules to cytotoxic CD8+ lymphocytes, which kill neurons through the perforin-granzyme B and Fas ligand - Fas receptor axis.
- Many known forms of T-cell mediated AE are caused by the induction of an autoimmune response against neuronal proteins by tumors (onconeural antigens).
o These forms are called paraneoplastic AE. - In paraneoplastic AE, the infiltrating T cells cause neuronophagia (phagocytosis of dying cells by microglia), granzyme B neurotoxicity, neuronal loss, and gliosis (hypertrophy of glial cells).
- Antibodies frequently described in paraneoplastic limbic encephalitis (LE) are anti-Hu (most common, often originating from small cell lung cancer), anti-Ma, and anti-CRMP5.
Tcell AIE - diagnosis + prognosis
- Exclude other diseases that might cause encephalitis (MS, viruses, etc)
- MR imaging is the modality of choice for demonstrating the pathological changes associated with AME.
- Cancer screening
o Paraneoplastic disorders are, in general, autoimmune disorders that are triggered by tumors. In many cases the target antigen is expressed by tumor tissue, such as HuD proteins in small cell lung cancer and NMDARs in ovarian teratoma.
o In these patients it is likely that presentation of the antigen in the context of the tumor triggers the autoimmune response leading to onconeural antibodies –> serum testing for Ab - harder to treat than Ab-mediated but can be treated
- prognosis depends on oncological considerations and advancement of AIE
- irreversible damage can be done due to AIE so early treatment is needed to give a good prognosis –> no treatment death with few years (relapsing can occur)
Tcell AIE - treatment
- First line therapy:
o Corticosteroids: (first choice) - Second line therapy:
o This treatment line starts if there is no clinical improvement after 2-4 weeks after administering first line treatments.
o Cyclophosphamide
disrupts DNA replication → inhibits cell proliferation → depletion of T cells - Third line therapy:
o 20-30% of (t-cell) AE patients do not respond well to first and second line treatment, therefore requiring third line therapies.
o Some third-line therapies for these patients are suggested, but, so far, there are no established guidelines for specific treatment regimes.
Tocilizumab= anti-IL-6 mab
Ab AIE - symptoms
- Clinical presentation is diverse and dependent on particular neuronal antigen and specific brain region targeted
- Symptoms include:
o Acute and subacute onset of rapidly progressive diverse neurological and neuropsychiatric symptoms
Psychiatric and behavioral disturbances
Cognitive dysfunction
Intractable seizures
Involuntary movements
Sleep disturbances
Autonomic instability
Decreased level of consciousness
Ab AIE - patho mech
- Abs are thought to either penetrate a leaky blood–brain barrier (BBB) or to be synthesized mainly within the intrathecal compartment:
Ex.: paraneoplastic-AE
(1) In NMDAR (mainly an ovarian teratoma) or a herpetic infection can precede the onset of the disease. In the peripheral circulation T-helper lymphocytes interact with B lymphocytes, -> B lymphocytes activated -> somatic hypermutation and differentiation -> auto-Antibody production
(2). Antibodies against neuronal surface Antigens may subsequently reach the central nervous system by crossing the blood–brain barrier (BBB) at sites of increased permeability (3a).
(3b) It is also likely that activated B-lineage cells are able to cross the BBB actively and undergo the same differentiation process within the central nervous system, contributing to the intrathecal pool of auto-antibodies
(4) When the Antibodies reach target, the normal function of the surface Antigen (usually a ionic channel; 4a) can be altered by different mechanisms. The Antibodies may prevent the binding of the channel ligand (blocking; 4b); some Abs cause cross-linking and internalization of receptors and thus depletion from the cell surface (4c); finally, Abs may activate the complement cascade and induce neuronal death (4d)
Ab AIE - treatment
- First line treatment – corticosteroids combined with either IVIg or plasmapheresis (1-2 weeks of treatment)
- Second line treatment – given as a monotherapy or in combination for refractory disease activity 1 to 2 weeks after completion of first line treatment (Rituximab IV for 4 weeks, Cyclophosphamide IV monthly for 3 to 6 months)
- Maintenances treatment: Rituximab, repeated every 6 months; IVIg every 2 to 4 weeks; mycophenolate mofetil 500 to 3,000 mg a day; Azathioprine daily; cyclophosphamide daily orally
Ab AIE - prognosis
- Relapses might occur after resolution of AIE
- Type of AE:
o Traditional Intracellular (e.g. anti-Hu or ANNA-1 and anti-Ri or ANNA-2): driven by primarily CD8+ T-cell cytotoxic response have a poorer prognosis, with a limited response to immunotherapy
Usually related with paraneoplastic disorders –> worse prognosis depending on oncological considerations
o Ab-meidated: cell surface/synaptic antibodies appear to be directly pathogenic and are more responsive to multimodal immunotherapies –> type determines prognosis (usually can be cured)
MS - general
- MS is a chronic, inflammatory and demyelinating disease of the CNS, affecting more than 2.5 million people worldwide.
- Onset usually occurs between 20 and 40 years of age
- It is the most common cause of neurologic disability in adults
- Affects more women than men (2/2.5:1 ratio)
- Many genetic and environmental factors are associated with MS (smoking, Epstein-Barr virus - EPV)
MS - symptoms
MS can affect any part of the brain so the symptoms can be variable
* Visual impairments such as - unilateral optic neuritis (blurred vision with associated pain)
* Focal sensory disturbances (limb paresthesias – tingling and numbness)
* Episodic bursts of fatigue
* Intestinal and urinary system disorders
* Motor weakness, ataxia
* Cognitive impairment (e.g. memory, attention)
* Depression, anxiety
MS - types
- In 85% of patients, MS starts as a “relapsing-remitting” form (RRMS) – the presence of clinical, acute unpredictable relapses usually followed by functional recovery: activated immune cells cause lesions in the CNS which generate symptoms
- After a variable period of time (some papers say 10-15 years), 50% of RRMS patients enter a progressive phase of disease called “secondary-progressive” MS (SPMS).
- The remaining patients follow a progressive course from the outset – “primary-progressive” MS (PPMS) - PPMS which largely affects the nerves of the spinal cord.
- rarest type “progressive-relapsing” MS (PRMS).
MS - patho mechs
- aetiology = unknonw (suspected EBV involvement)
- In the case of viral-induced molecular mimicry: APCs activate anti-myelin CD4+ T cells which then differentiate into T helper (Th) cells - Th1, Th2 and Th17 drivers of MS
- Autoreactive T cells (Th 1 and Th 17) –> extravasation into CNS
- T cell and released chemokines and cytokines (IL-17, INFγ and TNF-α) –> permeabilise BBB
- Th17 releases a large number of pro-inflammatory cytokines (IL-17 – promotes CNS inflammation by priming the BBB, allowing even greater permeation of autoreactive CD4+ T cells into the CNS);
- Th1 release interferon gamma (INFγ) or type II interferon and TNF-α → they promote inflammation by suppressing Th2 differentiation
- B-cells enter the CNS (intrathecal germinal centres) and turn into plasma cells → plasma cells produce anti-myelin antibodies.
- The antibodies activate the complement system (to some extend) → MAC formation → damage to myelin and demyelination
- Monocytes also enter and become active macrophages → phagocytosis of the myelin
- CD8+ T cells (cytotoxic T cells) are also involved.
- Fas ligand (FasL) can be expressed on cytotoxic T cells and bind to Fas receptors on oligodendrocyte cells which triggers apoptosis in those cells.
- TCR binds to myelin antigens in MHC1 (on oligodendrocytes) –> apoptosis (granzymes and perforin)
MS - diagnosis
- There are no markers specific for MS diagnosis, therefore it mainly relies on medical history and neurological exams.
- The attacks are defined as new neurological deficits that last longer than 24 hours and can be associated with an anatomical localization independent of a fever or infection.
- The most important paraclinical test to confirm the diagnosis is an MRI with an intravenous contrast agent containing gadolinium.
- By using an MRI you can see if there was a single anatomical region involved making it a monofocal attack or many regions making it multifocal.
- Another important examination to conduct is a lumbar puncture for CSF and CSF biochemistry
NMO - general
- NMOSD is a spectrum of rare, demyelinating disorders affecting the optic nerve, brain stem and spinal cord. It is thought that these disorders affect between 1 and 10 in every 100,000 people, with the most common disorder within the spectrum being simply Neuromyelitis Optica (NMO).
- NMO impacts more women than men with a ratio potentially as high as 9:1, and an average age of onset of 35.5, older than for MS.
NMO - symptoms
- NMO manifests as inflammation of the spinal cord (myelitis), optic nerve (optic neuritis), and brainstem.
- Optic neuritis results in symptoms of visual impairment, with loss of visual acuity, visual field, or color vision all possible as a result.
- Myelitis can result in reduced sensation in the limbs, paralysis, and muscle weakness, as well as other impacts based on lesion location like loss of bladder and bowel control, and erectile dysfunction.
- Lesions in the brainstem can similarly have an impact based on location, including those on the medulla causing intractable hiccups, nausea, and vomiting.
- Additionally, fatigue is a common symptom, affecting more than 75% of people with the disorder.
NMO - pathophysiology
- Aetiology= unknown
- Anti-aquaporin4 antibodies –> expressed on astrocyte endfeet –> BBB breakdown
- IgG1/3 –> complement, antigenic modulation, ADCC, phagocytosis
- BBB breakdown –> neuroinflammation and damage (necrosis)
- Dysfunction of astrocytes –> glutamate homeostasis dysregulation –> glutamate excitotoxicity
