Neuropathology: 2023-2024 Lecture Notes PDF

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2024

Mayia My

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These lecture notes cover various topics in neuropathology, including multiple sclerosis, headache types (migraine, tension, cluster), and cranial neuralgia. The notes also touch upon Amyotrophic lateral sclerosis and NMOSD/MOGAD. The document is structured around topics and relevant content, like definitions and epidemiology.

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Neuropathology Prof. Sartori 2023-2024 By Mayia My 1 Table of Contents Neuropathology...................................................................................................................... 1 Multiple sclerosis................................................

Neuropathology Prof. Sartori 2023-2024 By Mayia My 1 Table of Contents Neuropathology...................................................................................................................... 1 Multiple sclerosis.................................................................................................................... 3 Craniofacial pain: migraine, tension headache, cluster headache and trigeminal neuralgia...... 33 Headache............................................................................................................................. 34 Migraine aura........................................................................................................................ 36 Tension headache................................................................................................................. 40 Cluster headache.................................................................................................................. 41 Cranial neuralgia................................................................................................................... 45 Amyotrophic lateral sclerosis................................................................................................ 49 NMOSD & MOGAD................................................................................................................. 56 NMOSD................................................................................................................................. 56 MOGAD................................................................................................................................. 62 2 Multiple sclerosis Definition MS a4ects young people. There is a cure for this disease. There is a di4erence between this disease and Alzheimer’s disease. For MS, there is a medication that can change the long term prognosis and daily life of young people. MS is an autoimmune chronic inflammatory and neurodegenerative disease of the CNS. It a4ects the brain and spinal cord, but it preserves the nerves. The main characteristic of the MS is demyelination and axonal loss. Epidemiology A1ects 2-3 million people worldwide. Most common cause of non-traumatic disability in young adults, excluding traumatic cuases. Incidence 3/100.000. Prevalence100/100.000 (50-300); in our clinic 450-500 patients. There is a big di4erence between incidence and prevalcence because life expectancy is almost normal. Let say that there are 10 new cases every year, but these cases are added to the other 500 and the people are dying only when they are old. Mean age at onset 30 y (20-45). It is the most common cause in the young people. Paediatric onset: increasing incidence. Possible onset also >60 y. It is an autoimmune disease, which usually a4ects more women than men. There is an increased incidence in womenà F:M=2,5:1 [Koch-Henriksen, 2010; Orton,2006]. Global distribution of generally increases with increasing distance from the equator, although there are exceptions. The countries closer to equator have a lower incidence. This is because of the greater ability to diagnose the disease and because of the low vitamin D levels that are correlated with multiple sclerosis. High perveance in Sardinia, because there is an overexpression of cytokine BAFF that is associated with autoimmune risk. This association with the cytokine is due to the fact that it is protective against the malaria. Therefore, there is a selection for the protection against of malaria, but it exposes to the increased risk of autoimmune diseases, such as MS. Etiology and pathogenesis MS is a multifactorial disease. There is an interaction between predisposing genetic substrate and environmental factors. Environmental factors o Pathogens: direct damage from immune cells during acute infection or molecular mimicry [Gran, 1999]: Epstein Barr Virus (EBV), cytomegalovirus (CMV), Herpes 3 Simplex Virus (HSV). EBV is a pathogen that causes mononucleosis. However, not everyone develops the disease. o Low Vitamin D levels (also progression)àfrequently seen with people in MS. There is an increased risk of disease progression, such as worsening of degeneration. o Pediatric obesity o Cigarette smoking (also progression) In the longitudinal study of military, more than 10 millions of young adults were tested for EBV. They were followed during the years and it was shown that 900 people developed multiple sclerosis and were positive for Epstein Barr virus. This suggests that EBV is not su4icient, but necessary for the development of the disease. This provides how can it be prevented such as by vaccination. Genetics o Association between HLA region of chromosome 6 and development of autoimmune diseases. o MS: association with the serotype DR2 (now preferentially covered by HLA-DR15 and HLA-DR16 serotype group) has been known since the 1970s. Carriers of the HLA DRB1*15:01 allele are three times more likely to develop MS. o Genome-wide association studies (GWAS) identified numerous independent associations within the extended MHC region, including some within class I genes and the non-classical HLA region. o The HLA locus accounts for 20–30% of the genetic susceptibility in MS. o Other studies identified genes associated with immune response. o Twins concordance: dizygotic: 2-5%; monozygotic: 20-30%. o Absolute risk for 1st degree relatives: 20-40x compared to general population. o Disease susceptibility is inherited, not MS. Gross anatomy Multifocal areas of demyelination are called plaques, lesions. In MS patietns there are more than one area. o Location: all CNS (brain, brainstem, spinal cord). They are 72 hours: status migrainosus). They need to stop and rest alone in a dark room, in silence, because migraine is almost always accompanied by extremely sensitivity to light, to sounds, or to smells. Migraine: postrome After the headache, there is thpost-traumatic stress disorder. 80% of patients May be long-lasting (up to 48 h) Fatigue Depression/euphoria Inability to concentrate Diagnosis Correct diagnosis is fundamental for di1erential diagnosis vs: o Other primary headaches (tension headache, cluster headache etc). o Secondary headachesàexclusion of severe conditions. It is based on: o Clinical presentation o Neuroimaging: in particular for cases with «red flags» The first one, we have to exclude secondary headaches. The second one, we have to correctly classify the headache, in particular, compared to the other primary headaches. We have to diagnose it with a clinical presentation, and if there are red flags we need CT or MRI, so we need neuroimaging to help us in excluding secondary headaches. Treatments Symptomatic treatments: for the attack, to be taken at the beginning of the headache 38 Preventive treatments: prophylactic medication, for patients with frequent and disabling migraine, to be taken continuously for several months in order to reduce severity and frequency of the attacks So we have to give a medication that is not only on demand, but that must be taken for some month in order to reduce, in the future, severity, frequency of the pain, because we have patients that have one or two episodes a month, they do not need preventive therapy. In cases of three, four attacks a week, this is completely intolerable so we need to prevent it. Symptomatic treatments Nonsteroidal anti-inflammatory drugs (NSAIDs): e.g. ASA, diclofenac, ibuprofen, ketorolac, naproxen. They can cause problems, such as gastric problems, bleeding, and so on. Analgesic combinations: acetaminophen/coidein (®Tachidol), Indomethacin/prochlorperazine/ca4eine (®Difmetré) Triptans (5-HT1B/1D agonists, serotonin receptor agonists at blood vessels and nerve endings in the brain): Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan. Tryptans do not work, for example, in tension headache. This is the reason why we have to diagnose correctly the headache because otherwise we give this medication to the wrong patient. The di4erence between all these tryptans here is simply the half-life. So we need, obviously, short-acting medication for short attacks and long-lasting medication for long attacks. Ergot alkaloids (activation of serotonin, noradenergic and dopaminergic receptors): dihydroergotamine Gepants (calcitonin gene-related peptide (CGRP) receptor antagonists): Rimegepant, Ubrogepant Ditans (5-HT1F agonists) Lasmiditan We have also to consider not only the type of medication, but also the route of administration. Root of administration such as nasal spray, subcutaneous injection, intramuscular injection or i.v.) can increase e1icacy and reduce the onset of drug action. Antiemetic medications (e.g. metoclopramide) are useful to treat nausea and vomiting, often associated to migraine, moreover they can increase pain killer e4icacy. Chronic use (abuse) of medication can cause headacheàmedication-overuse headaches (MOH). There are patients that take a lot of pills every week and this abuse is the real cause of their headache and we need to admit them at the hospital for some days in order to detox. Preventive treatments Avoid triggers In case of frequent, disabling attacks or attacks accompanied by neurologic deficits, it is appropriate to introduce a prophylactic treatment. The first list here is the traditional list of medications that are not specific for migraine, but are medications that are used for blood pressure, for depression, for epilepsy, and they can be used also for prevention of headache. o Beta-blockers: metoprolol,propranolol o Calcium channel blockers: flunarizine, verapamil o Anti epileptic drugs: valproicacid, topiramate o Anti depressants: amitriptyline,nortriptyline,butalsofluoxetine,paroxetineandsertraline Botulinuntoxin (OnabotulinumtoxinA)for chronic migraine. 39 Monoclonal antibodies anti CGRP ligand or anti CGRPreceptor are administered subcutaneously, monthly, or intravenously every three months, and they do work very well. They are very expensive, so they can be used only if the first-line treatments have a failure. o Erenumab 70 - 140 mg, sc every 28 days o Fremanezumab (AJOVY) 225 mg, sc monthly o Galcanezumab (EMGALITY) 120 mg, sc monthly o Eptinezumab (VYEPTI) 100 mg, i.v every 3 months Tension headache Epidemiology Most common headache type 85% of general population at least 1/year F>M Clinical characteristics Pain is described as pressing or tightening (non-pulsatingquality), a feeling like a tight band around the head Often bilateral Severity: mild to moderate, rarely severe (usually do not interfere with daily activities) Rarely photophobia or phonophobia No nausea o rvomiting (anorexia may occur) Not worsened by physical activity No prodrome Duration: 30 minutes to7 days Variable frequency May occur acutely under emotional distress Tension headache: trigger points Often associated to presence of trigger points (TrPs) in several head and neck muscles)àdiagnostic criteria: tenderness in a hyperirritable spot within a palpable taut band, local twitch response elicited by snapping palpation, and elicited referred pain with palpation. The trigger points are located in the muscle around the head, in particular, trapezius, suboccipital muscles, temporalis, pericardium, mastiandeus, splenius, and the ventricitae. You press the points, and you evoke the pain, and you feel the tenderness. Pathogenetic hypothesis 1. Reduced pain sensitivity threshold 2. Proprioceptive stimuli originating temporally or cervically are poorly interpreted by the brain 3. Reduction of serotonin levels 4. Nociceptor hyperexcitability Diagnosis (the same!) Correct diagnosis is fundamental for di1erential diagnosis vs: o Other primary headaches (migraine, cluster headache etc) o Secondary headaches0àexclusion of severe conditions It is based on: 40 o Clinical presentation o Neuroimaging: in particular for cases with «red flags» Treatments Symptomatic treatments: o Analgesics/NSAIDs o Physiotherapy o Muscle relaxants (e.g. tizanidine) Preventive treatments: o Antidepressants o Tricyclic antidepressant (amitriptyline,nortriptyline) o Venlafaxine,mirtazapine In this case, the symptomatic treatments are simply analgesics and anti-inflammatory drugs, but also physiotherapy and muscle relaxant, like tizanidine. In this case, there is no possibility to use medications like triptans. For preventive treatments, also in this case, there are no so many medications to use. In particular, the only medications are tricyclic antidepressants. If you have a headache, maybe you went to the neurologist and some neurologist prescribed you some other products that are not medicines, such as bartenic acid or other other substances. They are very useful as well. Cluster headache Defined as «suicide headache» One of the trigeminal autonomic cephalalgias (TACs): unilateral periocular pain associated with homolateral autonomic system symptoms Prevalence 0.7/1000 M:F=5:1 Age 20-40 y Familiar in 10% of cases, probable genetic predisposition (first-degree relatives have a 14-39- fold significantly increased risk of cluster headache). Cluster: headaches occurring several times a day, for weeks to months with remissions of months to years. It is calleed cluster because we see headaches that occur several times a day for weeks or months, but there are remissions that can last from months to years. So, there is a cluster of headaches. This author describes pain like a demon punching me in the eye. So, think about it and remember this picture. This is exactly the representation of this pain, extremely painful. It's unilateral, sharp, stabbing, severe and it is associated with autonomic system symptoms of the same face, of the same part of the face. Clinical characteristics Unilateral periocular pain, sharp and stabbing Severe Associated with homolateral autonomic system symptoms Duration: 15-180 minutes Frequency: 1 attack every other day to 8 times/day 41 Autonomic system symptoms When you see a patient with cluster headache, you recognize him because you see the autonomic symptoms on his face. What do you see? You see the lipidema, the mitomyosis, the endophthalmos, the tearing, the conjunctival injection, the renal area with nasal congestion, and finally, the fascial sweating. So, you see the face that is red, the eye is closed, there is tearing there. Due to parasympathetic hyperactivity. ter headache, we have to consider this complex interaction between three systems. Ptosis/lid edema Miosis, enophtalmos Tearing Conjunctival injection Nasal congestion and/or rhinorrhea Facial sweating Clinical presentation 90% of patients may become agitated and extremely restless. They are not able to stay like, you remember before, migraine patient, they stay in their room, dark, alone, silenced. They are absolutely not able to stay calm and rest. They need to walk, and they su4er, and they are extremely anxious, and the depression risk is there, and they have also thoughts of suicide, more than 50% of them. The attacks may wake them up during the night because they occur in particular times of the day, in particular moments of the day. Also, cluster headache, during the cluster, not in that three months or years, can be triggered by some foods or alcoholic take, high-intensity foods, cigarette smoking, but also as exposure to intense light, and finally, the altitude. Patients in extreme su1ering and anxiety (increased depression risk, up to 44% of patients) Suicidal thoughts (>50%) Attacks may occur at the same time(s) of day (may wake up the patient at night) Triggers (During «clusters») Alcohol intake (wine, bier) High histamine foods (fermented foods, mature cheese,...) Cigarette smoking Exposure to intense light Altitude Pathogenesis The neuroanatomical and functional systems involved in the pathophysiology of CH can be divided into three principal components; the interaction of these three components is responsible for the characteristic clinical presentation of CH. 1. The trigeminovascular system is of a migraine, that act together with a trigeminal autonomic reflex. 2. The trigeminal autonomic reflex 3. The hypothalamic system It is unknown how this type of headache is triggered, which is the real cause. There are two hypotheses, the central one and the peripheral one. o The peripheral one is an abnormal activation of the trigeminal vascular system that causes a 42 hyperactivation of the trigeminal autonomic reflex, and finally involves the hypothalamic system. o The central hypothesis, so a primary dysfunction of the hypothalamus, in particular the posterior part. 2. Trigeminal autonomic reflex Responsible for the activation of parasympathetic outflow, which causes typical trigeminal-autonomic symptoms such as lacrimation, conjunctival injection, and nasal congestion. o Activation of the second-order neurons of the trigeminovascular system, located in the cervical complex (trigeminal nucleus, C1, and C2). o These neurons send projections to the parasympathetic system through the superior salivary nucleus (pons). o These projections travel through the facial nerve and synapse in the sphenopalatine ganglion. o Postganglionic parasympathetic nerves innervate the lacrimal, nasal, and pharyngeal glands Neurons contain: o NO-synthase o Vasoactive intestinal peptide (VIP) o CGRP o Pituitary Adenylate Cyclase-Activating Peptide-38 (PACAP-38) In this case, the trigeminal nerve is involved together with other nerves, such as fascia nerve in the parasympathetic component, because the parasympathetic system does not originate with the trigeminal nerve, but with the level of the fascia nerve and the glossopharyngeal nerve. The exact mechanism of the activation of this reflex remains unknown, so we do not know if it is activated in the periphery or if there is a primary dysfunction in the hypothalamus. 3. Hypothalamic system Regulation of o Circadian rhythm o Neuroendocrine homeostasis o The autonomic nervous system The involvement of hypothalamus in cluster headache is clear because it can also explain why this type of headache is not always there, but it follows the circadian rhythm, so it comes during the night or in particular moments of the day, or also because it comes in particular moments of the year. So there is a circanual pattern and also a circadian pattern. In particular, in terms of circadian pacemaker, the key is represented by the suprachiasmatic nucleus of the hypothalamus, while we have also to remember that hypothalamic system is involved in the non-susceptive process because it receives also the projections from the so-called trigeminal hypothalamic tract. So we make trigeminal vascular system, then we have trigeminal autonomic reflex, then we have the trigeminal hypothalamic tract that projects to the hypothalamus that is involved both in pain and in circanal and circadian rhythm. Also plays a role in the nociceptive process of the trigeminovascular system and receives projections from 43 the trigeminal nerve via the trigeminal-hypothalamic tract; its role in cluster headache explains circannual patterns It may also contribute to the autonomic symptomsàparaventricular region of the hypothalamus has direct projections to the superior salivary nucleus, which projects to the sphenopalatine ganglion and facial nerve, lacrimal, nasal, and pharyngeal glands The suprachiasmatic nucleus of the hypothalamus isthe principal circadian pacemaker; it can be a4ected by photoperiodism (changes in sunlight duration during the day), which is strongly associated with increased CH attacks. The trigeminovascular system and the trigeminal-autonomic reflex not only modulate and potentiate each other through the release of vasoactive neuropeptides. The activation of the trigeminal-autonomic reflex may be secondary to an activation of the trigeminovascular system (peripheral activation of a4erent and e4erent trigeminalutonomic reflex branches is insu4icient to generate CH attacks) This seems to be the hypothesis that is most predominant. Indeed, if we activate from simply the trigeminal autonomic reflex, we are not able to trigger the cluster headache. So it seems that the primary role of the trigeminal vascular system is fundamental. The hypothalamus probably creates a brain state in which attacks are made possible (this may explain why cluster-like attacks can only be triggered with CGRP (which does not cross the blood-brain barrier) while CH patients are in the bout). If the hypothalamus does not allow the attacks to be possible, they do not start. This is the reason why we can act with our medication at the level of the trigeminal vascular system, at the level of the activation of the trigeminal reflex, and finally at the level of the hypothalamus. Symptomatic treatments Sumatriptan 6 mg sc or nasal spray. For the attack, we can use sumatriptan. Sumatriptan is one of the treatments that are used in brain, but in this case, in order to achieve the quickest response, we can deliver it not orally, but subcutaneously or as a nasal spray. Oxygen therapy: 100% oxygen delivered with a face mask, relieves pain within about 15 minutes. Ketorolac If ine4ective: o Intranasal lidocaine o Dihydroergotamine iv Preventive treatments All patients with this type of headache need to take preventive medications, because when the cluster is there, it's so di4icult to control it with the medications for the symptom. Verapamil 240-480 mg/day Prednisone 50-100 mg/day Galcanezumab (calcitonin gene-related peptide (CGRP) ligand) 300 mg sc/monthly, low e4icacy o Lithium 900 mg/day o Topiramate o Ergotamine 1-2 mg/day orally o Valproic acid The reason why the verocamil and lithium work is the fact that the hypothalamus is involved. The reason why oxygen works is the fact that this cranial autonomic symptom system is involved, in particular, through the action of spasoductive intestinal type, BLD. This is the reason why I explained all the neurological connections. 44 Cranial neuralgia Cranial neurologies must be di4erentiated between typical and atypical. Atypical ones usually are due to secondary type of neurologies. Atypical neurologies is not like a trigeminal neurology that comes along, but is due to another disease under it. Typical neurologies are short-lasting, stabbing, such an electric shock, usually unilateral, that follow in a very precise way the nerve distribution. Between one electric shock and the other, there are no symptoms. So, the inter-typical symptoms are absent. There is no epicyclic component. The disability is very high due to the severity of this electric shock. Which are the elements that have to indicate to us that this neurology is atypical? The fact that the pain is more di4use, is often bilateral, and can be treated, but not by the trigger points, but can be treated by stress or events and the fact that this pain does not follow precisely the nerve distribution, but is more di4use and the fact that we have also inter-critical symptoms, such as, tingling, numbness, or the fact that the epicyclic component is high, with low disability. Typical cranial neuralgias Intense, stabbing, electric shock-like pain, that follows nerve distribution Trigeminal neuralgia is the most frequent Other possible neuralgias: o Glossopharyngeal neuralgia o Occipital neuralgia o Nervus intermedius neuralgia Epidemiology The most common (90% of cranial neuralgias) Incidence: 3-5/100.000 45 M:F = 1:2 5°-6° decade; >50% over 75 y 95%: V2, 2° branch (maxillary) or V3, 3° branch (mandibular) 5% V1, 1° branch (ophthalmic). The involvement of the ophthalmic, is extremely rare, and usually is due to some other disease. So it's usually seen in secondary or occipital neurologies. This is a disease that a4ects older people, such as 60s, and over 70s. This is another great di4erence between neurologies and headaches, primarily headaches. Clinical presentation Severe and sudden facial pain. It described as a sharp shooting pain or like having an electric shock. Involves one or more divisions of the nerve (V1, and V2, less commonly V3). Unilateral Duration: short, unpredictable attacks that can last from a few seconds to about 2 minutes May occur dozens times a day NO associated neurological deficits NO autonomic system symptoms Triggers We can trigger this type of headache, this type of neuralgia, with trigger points. Painful attacks may occur spontaneously but are more often associated with a specific stimulus in a “trigger area” : o V1: the eyebrow (medial part) o V2: the upper lip and nasal wing o V3: the lower lip or lower molar teeth Can be triggered by: touching/washing the face, shaving, chewing, speaking, brushing your teeth, or yawning So a patient with this type of neuralgia can experience this shock, this electric shock, not only if they push the trigger points, but also simply touching the face, shaving, washing, chewing, speaking, yawning. The typical appearance of a patient with trigeminal neuralgia in this male is unshaved, because he cannot shave. Or maybe he can shave only on one side of the face. Pathogenesis Why cannot we see trigeminal neuralgia? There are some hypotheses. First one is a damage, if there is nothing in the MRI, I mean, of the myelin sheath of the nerve. Damage in the myelin sheet of the nerveàaltered transmission. Neurovascular conflictàmost common. There is an artery that is exactly very close to the nerve, and this contiguity causes an irritation of the nerve. o Compression of the nerve (V2 and V3) by the superior cerebellar artery- SCA or antero-inferior cerebellar artery-AICA (V1). This type of compression can be there since when we are born, so it can be congenital, but it can also happen in case of atherosclerosis or changes in the artery. This is the reason why usually the onset of this disease a4ects people that are older. o Congenital o due to atherosclerosis. Diagnosis Di1erential diagnosis with: o Primary headache, in particular: § Cluster headache § Trigeminal autonomic cephalalgias( TACs) o Secondary neuralgias 46 Imaging (MRI) in this case is important not only for di4erential diagnosis, but also to detect a neurovascular conflict To diagnose, first of all, excluding secondary headaches and distinguishing this type of headaches, this neuralgia, to the other primary headaches. In this case, MRI becomes particularly important, because we are not only looking for something that is not there, so to exclude something going on, but also we are needing the MRI to look for the conflict, because this can be tricky. The yellow arrow, there is just the nerve, normal nerve. On this side you see the nerve, but on the nerve there is this artery that creates a conflict, a compression. Think about a secondary trigeminal neuralgia when... There are moments, there are particular clinical presentations that suggest to us that we have to think about secondary trigeminal neuralgias. So, not the secondary neuralgia that comes due to the conflict, but some elements that suggest to us that there is something going on in the brain. Onset F (1,5:1) Onset 60-75 y The incidence is 2 to 4 per 100,000 every year, and the prevalence ranges from 6 to 8. What does this suggest to you? Prevalence and incidence are almost the same. Delay between symptoms onset and diagnosis: 10 months o Progressive course o Death in 2-5 years (25% still alive after 5 y, 3 metameres) Area postrema syndrome (unexplained and persistent hiccups or nausea and vomiting) Acute brainstem syndrome Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD typical diencephalic lesions (hypotension, amenorrhea, and the syndrome of inappropriate antidiuretic hormone) secretion has been observed in 3.4% of case Symptomatic cerebral syndrome with NMOSD typical brain lesions 19 1. NMOSD: optic neuritis 45% is presenting feature. 60% occurs during the disease course. Compared to MS-related optic neuritis, is more likely to be bilateral or atypical (i.e., atypical for MS), chiasmatic involvement. More severe vision loss Recovery and functional prognosis generally poor 2.Myelitis 85% of patients 59 Involvement is often longitudinally extensive transverse myelitis (LETM), defined as a cord lesion spanning more than 3 vertebral lengths to fulfill the criteria Severe and with poor recovery compared to MS. Silent lesions involving the spinal cord or brain are rare in NMOSD (and MOGAD) compared to MS. Both for MOGAD and MMO, silent lesions are not so frequent, while in MS silent lesions can be very frequent. 3. NMOSD: area postrema Area postrema is the emetic reflex centre in the base of the fourth ventricle; it controls physiological processes such as vomiting and hiccups. The diagnostic criteria for AP syndrome (APS) include acute or subacute intractable nausea, vomiting or hiccups for up to 48 hours without an alternative explanation or resolution with symptomatic treatment. 15-40% of patients 10% presenting clinical feature In the left in a A, there is a longitudinally extensive myelitis. Here is a very big myoptic ulcer. Here we have the arapostrema involvement both in the saggital and in an axial view. 60 Diagnosis (beyond MRI) For the diagnosis of this disease a MRI is needed. However, the antibodies need to be tested. The best test is the live cell base assay and we need to test them in the serum and while a CSF is less important. Detection of AQP4-IgG (best assessed using live cell-based assays) in serum (rather than CSF). We always test also the CSF. CSF analysis: o CSF pleocytosis of more than 50 leukocytes including neutrophils over 5/uL during acute attacks. o 40% of patients can have a normal CSF white cell count. o CSF-restricted (Type2) oligoclonal bands present in approximately 10-20% of patients (vs 85% in MS). Prognosis 90% relapsing disease course. Clinical deterioration in NMOSD can be irreversible with stepwise accumulation of deficits with subsequent relapsesàimportance of preventive treatments! In this disease we hope to have a complete recovery after the first relapse, but it does not always happen. We have absolutely to avoid the second relapse. It is mandatory, much more than in MS. This is the reason of the extreme importance of the preventive treatments. Treatments Treatment of relapses: similar to MS (i.v. high dose steroids, plasmapheresis) Preventive treatments: o Old treatments: azathioprine, rituximab and mycophenolate mofetil (MMF). o New treatments, recently approved: inebilizumab, satralizumab and tocilizumab, eculizumab. The IL-6R blockers (satralizumab and tocilizumab) (A) suppress di4erentiation of AQP-IgG antibody secreting cells (ASC), as well as generation of pro- inflammatory Th17 T cells and M1 macrophages in favour of regulatory T cells and M2 macrophages. Rituximab (B1) kills cells expressing CD20 (mainly naïve and memory B cells, but also some T cells). Inebilizumab (B2) depletes a wider proportion of the B cell repertoire expressing CD19, including some antibody secreting cells. Both rituximab and inebilizumab deplete antigen presenting memory B cells. Eculizumab (C) blocks the complement cascade by binding complement component 5 (C5), halting generation of membrane attack complex (MAC) through C5b and recruitment of pro-inflammatory cells through C5a. These are extremely expensive medications and are very rarely used, because fortunately rutuximab that is much cheaper works very well in these patients. Symptomatic treatments Similar to MS. Nevertheless, compared to MS, pain is much more common and severe; It represents the most distressing symptom in NMOSD. This has been hypothesized that maybe this pain is 61 not only due to the lesion of the spinal cord, but it is due to a dysfunction of the nerves of the astrocytes that contribute to the extreme perception of pain. MOGAD Myelin oligodendrocyte glycoprotein (MOG): 0.05% of myelin proteins Highly immunogenic Function not fully elucidated; it may act as a cell adhesion molecule, regulate microtubule stability, and modulate myelin immune interactions. MOG Ab associated disease (MOGAD) Recently described CNS autoimmune disease. Involves: o Optic nerve o Spinal cord o Brain Clinical presentation may resemble NMOSD. Epidemiology 50% pediatric onset May be monophasicàone shot and never comes back without treatment. F:M=1:1 (vs SM 3:1, NMOSD 9:1) Incidence: 1.6/million persons/y (children, 3.1/million; adulti, 1.3/million) vs AQP4- IgG+NMOSD (0.4–7.3/million) vs MS (7– 144/million) Pathology MOGAD pathology is characterized by the coexistence of perivenous and confluent primary demyelination with partial axonal preservation and reactive gliosis in the white and gray matter, with particular abundance of intracortical demyelinating lesions. This occurs on the background of CD4- dominated T cell and granulocytic inflammatory infiltrates. Contrary to classical AQP4-IgG seropositive NMOSD, in MOGAD the expression of AQP4 is preserved. Predominantly cortical plaques that extend into the subcortical white matter (a–d, MOG; b and d schematic drawings, cortical demyelination: orange; white matter demyelination green;) and form multiple perivenous areas of demyelination in the adjacent grey and white matter (c, arrows). Activated microglia and macrophages form a rim at the lesion borders and show a perivenous accentuation (e, HLADR; rectangle in a enlarged in e) with MOG-positive demyelination products within the macrophages (f, MOG; arrows; rectangle in e enlarged in f). Some lesions show superimposed ischemic damage with tissue necrosis with massive infiltration of neutrophilic granulocytes (g, H&E). Profound perivenous deposition of activated complement complex is visible (h, C9neo antigen). The inflammatory infiltrates mainly contain CD3 (i) and CD4 positive T cells (j), less CD8-positive T cells (k) and only few perivascular CD79a positive B cells (l). Scale bars a–d 1.2 mm; e 600 μm; f 30 μm; g–l 60 μm 62 Pathogenesis Autoimmunity in MOGAD is the outside-in model: where autoantibodies and activated immune cells in the peripheral blood cross the blood-brain barrier at the time of attack/relapse Infections could cause bystander activation and molecular mimicry Suggested mechanisms for MOG antibody pathogenicity include opsonization of MOG, complement activation (still debated), antibody- dependent cellular cytotoxicity (ADCC), and anti-MOG ab-induced intracellular signaling cascade MOG-IgG opsonizes MOG and could activate myeloid antigen-presenting cells (APC) through Fc receptor binding. These activated APCs can further stimulate MOG-specific T cells in the periphery or in perivascular spaces in the CNS. So the activation happens in the periphery. Then it is probably triggered by molecular mimicry phenomena. There very many patients with an infection that precedes the onset of the disease. Then the antibodies move to the CNS and the damage is performed to the CNS cells by all these mechanisms that involve the complement activation. However, compared to the NMOSD, the complement activation is still debated, while there is a antibody-dependent cell cytotoxicity and antibody-induced intracellular signaling cascades. The di4erence between MOGAD and NMOSD is that in this case. There is a bigger involvement of the T-cells, a damage that is performed directly to the oligotendrocyte compared to the astrocytes. The fact that in this case, the complement seems to be less involved. MOGAD: disease phenotypes 1. Optic neuritis(uni-orbilateral): severe visual loss, usually good recovery Bilateral simultaneous clinical involvement Longitudinal optic nerve involvement (>50% length of the optic nerve) Perineural optic sheath enhancement Optic disc oedema (radiologically visibile optic disc swelling and optic disc oedema on fundoscopy. The images show a bilateral and longitudinal involvement of both nerves. This here is a radiological visible optic disc swelling. This is an optic disc edema In fundoscopy. 2. Transverse myelitis: paraparesis, also asymmetrical, sensory level, sphincteric symptoms. Longitudinally extensive myelitis Central cord lesion or H-sign Conus lesion 3. Acute disseminated encephalomyelitis clinical syndrome characterized by a first polyfocal CNS episode from presumed demyelination that includes encephalopathy not explained by fever, systemic illness, or postictal features. 63 It requires MRI abnormalities that include large poorly demarcated lesions in the white matter with or without gray matter lesions acute and rapidly progressive, and it is characterized by multifocal neurologic symptoms 4. Cerebral monofocal or polyfocal deficits 5. Brainstem or cerebellar deficits 6. Cerebral cortical encephalitis often with seizures Disease phenotypes Brain, brainstem, or cerebral syndrome: radiological characteristics o Multiple ill-defined T2 hyperintense lesions in supratentorial and often infratentorial white matter. o Deep grey matter involvement. o Ill-defined T2-hyperintensity involving pons. o middle cerebellar peduncle, or medulla. o Cortical lesion with or without lesional and overlying meningeal enhancement. (J) T2-hyperintense pontine lesion (K) Bilateral T2-hyperintense lesions of the middle cerebellar peduncles (L) Bilateral T2- hyperintense cerebral lesions involving the thalami (M) Large ill-defined T2-hyperintense lesions involving supratentorial white matter (N) Cortical fluid attenuated inversion recovery hyperintensity with (O)associated leptomeningeal enhancement. Disease phenotypes In kids, there is a very frequent ADEMs. So the big, flat lesions. In adults, there is usually optic neuritis and myelitis. Diagnostic criteria This criteria has been proposed for diagnosis. In order to diagnose diseases, one of the core declinating events and the positivity of the antibodies need to seen If there is a clear positive, so there is the diagnosis. However, if there is not a clear positivity or if the antibodies are absent, the supportive clinical and radiological criteria are needed. 64 This is just a final comparison. MS, younger people, 20 to 40. For MOGA, we have also kids, so 0 to 40. For apoporin, a little bit older. Frequently, there is an inflammatory event, an infectious event, that happens before a MOGA disease, while this is not observed in animals as the MS. The most important thing is that MS is relapsing, similar to the others, but MOGA can be monophasic. The di4erence in the radiological features in the brain and in the spinal cord. The first is MOGA, the second is NMOSD and the third is MS. In MS, the optic neuritis is monolateral. The apoporin-4 can involve the chiasmatic area and in MOGA, it is bilateral and longitudinally extensive. Similarly, the spinal cord in MS has short lesions. In the other two diseases, there very big lesions. In MOGA, there is constant involvement. These are the brain pictures of the patients. 65 These final slides show the evolution of the brain diseases. MOGA can have a better prognosis compared to the other two and the lesions can completely disappear. In the other two diseases, unfortunately, there is a little bit of scar, so, there is an improvement. The lesions become smaller, there is less edema, but there is a little scar that stays there. With MOGA, there is a complete disappearance of the lesion. Similarly, also for the spinal cord. 66

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