Demyelinating Diseases, Neuro-Oncology, and Disorders of Neural Tube Closure and Other Congenital Malformations
Multiple sclerosis (MS) introduces the section on neuropathology because it is continuously redefining its place in neurology. Of all of the chapters to update, this seemed the most difficult because so many concepts have changed from the first edition of this book. Advances in understanding and treating the relapsing-remitting form have been staggering. The pathophysiology of primary progressive MS and acute disseminated encephalomyelitis (ADEM) has been better characterized and are no longer “neighboring parts of the same pathologic spectrum,” as we speculated before. Because it seemed easier to split what was not holding well together, the MS body of knowledge had historically suffered from a nomenclatural burst of diseases (Schilder’s encephalitis periaxialis diffusa, Marburg’s fulminant encephalomyelitis periaxialis scleroticans, and Balo’s encephalitis periaxialis concentrica). These fortunately have come to terms with their ancestral demyelinating roots by ultimately showing the “sharp-edged plaque” scar that the rest of the MS family carries. The Balo concentric plaques are more often present in persons of Asian descent with a monophasic course aligning with the nosology of ADEM.
At a basic level, the difference between ADEM and MS is that the former is a clinically isolated syndrome (popularized as CIS) and has yet to leave isolation and become recurrent, or MS. At a deeper level, ADEM is more “gray” (than “white” matter disease) and “confusing” (encephalopathy is common in ADEM; rare in MS). Furthermore, CIS does not necessarily mean ADEM, a second CIS may not represent MS (but, possibly, recurrent DEM, when the deficits are the same or multiphasic DEM when the deficits are different), and some CIS can now, by virtue of imaging support, be elevated to what amounts as a first MS episode. The latter is the most important of these uncertainties as the increasing range of disease-modifying therapies exercise a greater role when given earlier: the more CIS are treated, the lower the likelihood they will become definite MS.
The triumph of the MS “splitters” is neuromyelitis optica spectrum disorder (NMOSD). Longitudinally extensive transverse myelitis (LETM) and white matter lesions around the spinal canal and third ventricle, betrays NMOSD’s predilection for water channels. Although “neuromyelitis” was coined more than 100 years ago, it was not until recently that NMOSD became a distinct inflammatory demyelinating disease. Its unique pathophysiology led to the successful development of the first disease-modifying drug for one of the autoantibodies linked to this disorder, aquaporin-4, approved just prior to print (eculizumab, inebilizumab, and satralizumab are likely to follow).
Similar to the first edition, the major challenge in MS remains the lack of a single pathognomonic clinical feature or ancillary test. Diagnosis relies on integration of clinical, neuroimaging, and laboratory evidence and the exclusion of better alternative diagnoses. Some of the reasons for misdiagnosis include atypical presentations, lack of objective evidence on examination, and overreliance on MRI findings in the setting of nonspecific symptoms. MS may well be one of the most inappropriately overdiagnosed disorders.
Multiple Sclerosis
MS is a chronic demyelinating disease of the central nervous system (CNS), affecting the brain, spinal cord, and the optic nerves, resulting in injury to the myelin sheaths, oligodendrocytes, and, eventually, axons. The disease exhibits a north-south gradient, maintained among immigrants younger than 15 years. In 1996, four clinical phenotypes were recognized: relapsing-remitting (RRMS, 85%), secondary progressive (SPMS), primary progressive (PPMS), and progressive-relapsing (PRMS). Phenotypes have been subsequently amalgamated into relapsing-remitting disease, which includes clinically isolated syndrome (CIS) and relapsing-remitting MS, both of which are further subdivided into nonactive and active; and progressive disease, which includes primary progressive MS (PPMS) and secondary progressive MS (SPMS). PPMS is divided into active with progression or active with no progression; SPMS into not active but with progression and not active and no progression. Clinically definite MS (CDMS) can be made with a CIS if MRI defines dissemination in space (DIS) and time (DIT).
Multiple Sclerosis Diagnostic Criteria (Revised McDonald criteria, 2017)
| ||||||||||||||
MRI evidence of dissemination in space (DIS) is demonstrated by ≥ 1 T2 lesion (≥3 mm in long axis), symptomatic or nonsymptomatic, in at least two of these four locations: Periventricular, cortical or juxtacortical, infratentorial, and spinal cord. Currently a T2 lesion in the optic nerve does not count toward DIS.
MRI evidence of dissemination in time (DIT) can be established in one of two ways: (1) A new T2 hyperintense lesion or gadolinium-enhancing lesion when compared to previous MRI irrespective of timing; (2) the simultaneous presence of gadolinium-enhancing lesion and a nonenhancing hyperintense lesion on any one MRI.
| ||||||||||||||||||
MS affects women disproportionately. The risk is 2% to 4% in affected first-degree relatives with MS. Concordance in monozygotic twins is 30% to 50%. Of the 200 risk genes, the most significant is the HLA DRB1*1501 haplotype (OR ˜3). Other risk factors include Epstein-Barr virus (not clear for human herpes virus type 6 [HHV-6], CMV, or measles), high latitude, low vitamin D, smoking, obesity, and early adulthood.
Prognostic Factors in MS
|
Neuroimaging in Multiple Sclerosis
 A 17-year-old woman with facial pain, gait instability, and bilateral leg weakness. CSF showed oligoclonal bands. FLAIR MRI showed multiple hyperintense lesions in the periventricular and bihemispheric deep white matter, with additional involvement of the pons, left cerebral peduncle, bilateral middle cerebellar peduncles and proximal aspect of the medulla. |
 A 54-year-old woman with subacute onset of word finding difficulties and right-sided clumsiness. T1W postcontrast MRI shows a thick rim of irregularly enhancing left posterior frontal intra-axial mass, extending to the ependymal surface of the lateral ventricle. The peripheral rim of enhancement demonstrated restricted diffusion (not shown). Brain biopsy demonstrated demyelination, perivascular lymphocytic infiltrates, macrophages, and reactive gliosis. These findings are suggestive of the tumefactive form of MS. |
 A 51-year-old woman with a 6-year history of progressive ataxia, parkinsonism, and cognitive impairment consistent with PPMS. T2W MRI showed diffuse periventricular and deep white matter signal abnormalities with cystic degeneration of the white matter suggestive of the more severe,“cerebral form” of MS. Some of these lesions enhanced after gadolinium. |
Pathogenesis of Multiple Sclerosis
MS is characterized by inflammation, demyelination, and axonal injury. Although the etiology of MS is unknown, the immune system plays a central role in the pathogenesis of the disease. Clonal expansion of immunoglobulin-secreting B cells and plasma cells in the CNS results in the characteristic finding of CSF-specific oligoclonal bands. Past Epstein-Barr virus (EBV) infections, noted by a high anti-EBV nuclear antigen IgG titer and history of infectious mononucleosis, increases the risk of MS.
The MS lesion contains helper CD4+ (more concentrated in the perivascular cuff) and cytotoxic CD8+ T cells (widely distributed within the parenchyma), B cells (in the perivascular space and meninges), and macrophages attracted to the lesion. CD4+ T cells have two subtypes: Th1 and Th2, pro- and anti-inflammatory, respectively. Th1 cytokines include IL-2, IL-12, IFN-γ, and TNF-α, which activate macrophages for cellular immunity. The Th2 cytokines are IL-4, IL-5, and TGF-β, which activate immunoglobulins-generating B cells for humoral immunity. Blood-brain barrier disruption allows activated T cells to gain access to the CNS. Cell adhesion molecules such as ICAM-1, VCAM-1, and metalloproteinase 9 (MMP 9) facilitate entry of T-lymphocytes into the brain. Inside the CNS, specific antigenic peptides are shown in major histocompatibility complex (MHC) molecules to T cells. CD8+ T cells recognize them through Class I MHC molecules in neurons and oligodendrocytes; CD4+ T cells, in the perivascular cuff, recognize antigens using Class II MHC antigens on dendritic and microglial cells, and release the cytokines that attract macrophages to the lesion.
Drugs that limit T cell access to the CNS can reduce or eliminate new MS lesions. Also, a role of B cells is supported by the success of B cell-depleting antibodies in limiting MS lesion formation and clinical disease activity. Because the clinical response to B cell depletion (as early as 8-12 weeks) is faster than that required to reduce oligoclonal IgG bands, it seems more likely that B cells relevance is in antigen presentation to helper T cells and in cytokine production.
Other pathogenically relevant elements may be activation of cells of the innate immune system (microglial activation may represent the earliest stage of lesion development), disturbance in the blood-brain barrier, and leptomeningeal inflammation. Despite relative axonal sparing in demyelination, axonal transections are frequent.
Three pathological patterns have been identified. Pattern 1 shows inflammatory demyelination with prominent macrophages and sharp borders. Pattern 2, the most frequent, also has well-defined demyelination and prominent lymphocytic and macrophage infiltration with marked complement deposition (the lesion edges correlate with MRI Gd enhancement). Pattern 3 has less well-defined borders, far fewer oligodendrocytes, and less remyelination. The antibody/complement-mediated nature of Pattern 2 may be why there is greater response by these patients to plasmapheresis.
CSF and serum neurofilament light chains are promising biomarkers of neuroaxonal injury. OCB are nonspecific for MS (infections can cause the same pattern).
Important Variants of, or Related Entities to, Multiple Sclerosis
Optic Neuritis and Acute Transverse Myelopathy
The 5-year risk of developing MS after the diagnosis of optic neuritis (ON) is 16%. The risk increases to 51% if MRI shows two or more T2W lesions. If both MRI and CSF are normal, the likelihood of ON or any other monophasic syndrome to evolve into MS is very low. The risk of MS in acute transverse myelopathy (ATM), more common among Asians than Caucasians, is 2% to 8% in complete transverse myelopathy or transverse myelitis (TM) and up to 80% in incomplete TM. Patients with ATM may respond to high-dose methylprednisolone and plasma exchange but not to intravenous immunoglobulin (IVIG).
Neuromyelitis Optica Spectrum Disorder
Neuromyelitis optica spectrum disorder (NMOSD) is a distinct inflammatory demyelinating disease characterized by bilateral or recurrent optic neuritis with or without longitudinally extensive spinal cord lesions (>3 vertebral segments, centrally located). Episodes of intractable nausea or vomiting and hiccups result from area postrema involvement. Other clinical features include acute brainstem syndromes, narcolepsy, acute diencephalic clinical syndromes, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, myeloradiculitis, and encephalopathy resembling ADEM. CSF shows neutrophilic pleocytosis (>50 WBC/mm3 or > 5 neutrophils/mm3) and proteinorrhachia, often without OCB. NMOSD may be due to autoantibodies against myelin oligodendrocyte glycoprotein (MOG, ˜8%) or aquaporin-4 in astrocytes (AQP4, ˜73%). MOG-IgG syndromes have a phenotype that includes optic neuritis (most cases), encephalitis with brain demyelinating lesions, and/or myelitis, the term myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-associated optic neuritis, encephalitis, and myelitis (MONEM) has been proposed. AQP4-NMOSD is more frequent in women and African-Americans, affecting the periependymal region of the third ventricle, the hypothalamus (narcolepsy), medulla (nausea, vomiting, and hiccups), and spinal cord. AQP4 predicts poorer visual outcome and recurrence. Acute treatment is with glucocorticoids, IVIG, or plasma exchange. NMOSD may worsen with interferon β, fingolimod, and natalizumab. Eculizumab (Soliris), a complement inhibitor of C5 protein used to treat antiacetylcholine receptor (anti-AChR) antibody-positive myasthenia gravis, was recently approved for AQP4-NMOSD. It reduces the risk of recurrent attacks by 94%.
Acute Disseminated Encephalomyelitis
ADEM is usually a monophasic postinfectious encephalopathy, more common in childhood, which may result from a transient autoimmune response toward myelin induced by molecular mimicry or activation of autoreactive T cell clones. Seizures, encephalopathy, basal ganglia/thalamic involvement, and tumor-like brain MRI appearance are more common in ADEM than in MS. The triggers of ADEM can be viral, such as mycoplasma (bilateral striatal necrosis), measles, varicella zoster (acute cerebellar ataxia), mumps, rubella, influenza, EBV, hepatitis A, and vaccinations against rabies (myelitis and myeloradiculitis), mumps, measles, and diphtheria. CSF shows pleocytosis with increased intrathecal IgG but no OCB. There is perivascular demyelination on pathology. Up to 20% of patients go on to develop pediatric MS, which has a greater relapse rate (more inflammatory) but slower rate of progression (less neurodegenerative) than adult MS. Presence of OCB are positive predictors and seizures and encephalopathy negative predictors of progression into MS.
Neuroimaging of Neuromyelitis Optica Spectrum Disorder
Spine MRI images of a patient with spastic tetraparesis with NMOSD-AQP4 positive antibody serology at presentation (upper row) and 4 years later.
 T1W, T2W, and postgadolinium MRI of the cervical spine shows an expansile T2 hyperintense lesion centered in the spinal cord, extending to the dorsal medulla superiorly and to T2-T3 levels inferiorly. The T2 hyperintense signal abnormalities involve most of the spinal cord diameter with some sparing of the periphery of the spinal cord. The spinal cord expansion is most prominent at the C2-C3 levels through the C5-C6 cord levels. There was associated confluent spinal cord enhancement involving primarily the dorsal columns with sparing of the anterior and lateral portions of the spinal cord, extending from the dorsal aspect of the medulla oblongata to the C7-T1 cord levels. |
 Same patient, 4 years later: T2W and postgadolinium MRI showed decreased interval T2 hyperintense signal within the cervical spinal with no enhancement. The cervical spinal cord shows interval reduction in caliber indicating atrophy. |
Important Imitators of Multiple Sclerosis
| |||||||||||||||||||||||||||||||||
Human herpes virus type 6 (HHV-6), the most neuroinvasive herpes agent, may cause febrile seizures and focal demyelination. VZV may cause leukoencephalitis in the latter.
Tropical spastic paraparesis is caused by human T cell lymphotropic virus type 1 (HTLV-1) infection, the first human retrovirus, and mainly affects women between 35 and 45 years of Japanese (20%) or Caribbean (5%) ancestry.
Behçet disease is a noninfectious multisystem inflammatory disorder of unknown etiology, common in males of Mediterranean countries along the Silk Road and Japan, characterized by vasculitic changes in multiple organs. It consists of a chronic relapsing combination of oral aphthous ulcerations, genital ulcerations, erythema nodosum, anterior and/or posterior uveitis, and/or retinal vasculitis. Attacks of Behçet disease become less frequent and less severe over time. Major morbidity results from ocular, vascular (venous sinus thrombosis [VST], increased ICP, headache, aseptic meningitis), or brainstem or corticospinal lesions (neuro-Behçet syndrome). Rare presentations include ICH from ruptured aneurysms, isolated optic neuritis, and a parkinsonian syndrome. CSF studies may show neutrophilic pleocytosis and proteinorrhachia. There may be intrathecal IgG but rarely OCB. MRI lesions in 50% of patients are restricted to the brainstem, diencephalon, and basal ganglia regions.
Susac syndrome applies to a combination of encephalopathy, visual field defects from branch retinal artery occlusions, and hearing loss, occurring in a monophasic, stroke-like onset, or progressive fashion. Women are more often affected than men (3:1). Headaches, cognitive impairment, behavioral problems, and seizures may occur. Brain MRI may show snowball-like corpus callosum lesions of the central fibers with relative sparing of the callosal periphery (unlike MS and ADEM). CSF shows mild pleocytosis and proteinorrhachia but without intrathecal IgG or OCB (also unlike MS).
Disease-Modifying Therapies for Multiple Sclerosis
The FDA has approved 15 disease-modifying medications for RRMS: 5 based on interferon beta; 2 on glatiramer acetate; the monoclonal antibodies natalizumab, alemtuzumab, daclizumab, and ocrelizumab (the first B cell-targeted therapy); the chemotherapeutic agent mitoxantrone; and the small-molecule oral agents fingolimod, dimethyl fumarate, and teriflunomide. Cladribine, fingolimod, siponimod, and ocrelizumab have been approved for SPMS; ocrelizumab for PPMS. Treatment is escalated, as needed and tolerated, to “no evidence of disease activity” (no new lesions, relapses, disability progression, and, more recently, tissue atrophy).
|
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
