Demyelinating Disorders

Clinical Features

Multiple sclerosis is a chronic, immune-mediated disorder for which the exact cause is unknown; it is not the result of direct viral infection. The highest incidence is in females, and this sex skew appears to be increasing. Onset of multiple sclerosis usually occurs in young adulthood, between 20 and 40 years of age with a global median prevalence of 33 cases of MS per 100,000 people, with significant differences between different countries. Due to increasing longevity of persons with MS, the prevalence and overall age of the MS population are also increasing.

While some patients are mildly affected, MS remains one of the most frequent causes of acquired disability in young persons. The clinical disease course of MS usually evolves over decades. The three types of established disease are relapsing-remitting, secondary progressive, and primary progressive, with some also considering clinically isolated syndrome (CIS) as an initial type of MS. The vast majority of MS cases are either relapsing-remitting or primary progressive, with 85 % of patients having the former type. Relapsing-remitting disease includes episodes of neurological dysfunction lasting at least 24 hours in the absence of fever or infection; episodes are distributed over time (two or more sets of symptoms 30 + days apart) and space (two separate locations in the brain/spinal cord) without other identifiable cause. The disease may be the typical relapsing-remitting type on initial presentation, but the majority of patients eventually enter a secondary progressive stage with few relapses, but cumulative deficits over time. With advanced disease, brain atrophy often occurs.

Older statistics suggested a grim overall long-term prognosis for the disease, but today, many patients are 20 + years into their disease before the use of a cane is necessary and a larger percentage of benign MS is being diagnosed. Clinical parameters associated with more aggressive disease course, either singly or in combination, include male sex, older age at onset (> 35 or > 40 years), severe relapses, frequency of relapses in the first 5 years, short interval between relapses, early accrual of disability, and Expanded Disability Status Scale (EDSS) ≥3 in the first year after disease evolution. About 7 % of MS patients meet the criteria for aggressive disease, defined as patients who reached an EDSS of 6 within 5 years, those with EDSS ≥6 at the age of 40 years, and those who entered secondary progressive MS within 3 years after relapsing MS disease onset.

Zeydan and Kantarci noted that “transition from the relapsing-remitting phase to the progressive phase in MS often happens in the fifth decade. In MS, structural central nervous system reserve decreases with aging and MS-associated mechanisms. While clinical and subclinical disease activity decreases with aging, the post-relapse recovery potential decreases with aging as well. Moreover, the efficacy of disease-modifying treatments declines with older age. Aging emerges as the ultimate target for prevention of progressive disease course, which is the most important determinant of disability worsening in MS.”

Early in the disease course, isolated lesions may be encountered in a patient that require time to pass before the full spectrum of disease is recognized and before confident diagnosis of MS, a disease defined as distributed in time and space, can be rendered. CIS represents the first attack that is clinically recognized. Radiologically isolated syndrome (RIS) is found in individuals undergoing magnetic resonance imaging (MRI) for non-MS symptoms who show a typical MS lesion on neuroimaging. RIS is a possible diagnosis because very typical neuroimaging features occur in most cases of MS and they can be distinguished from other demyelinating disorders, especially in later disease stages; thus, descriptions of these neuroimaging features are provided below for both early and intermediate/later stages of MS.

Clinical signs and symptoms of MS are varied. A prodrome is increasingly being recognized, but this consists of a relatively nonspecific constellation of signs and symptoms. No single feature is specific for the prodrome of MS. However, most studies agree that there is an increased use of the medical/mental health systems in the 5 years prior to the first diagnosed demyelinating event in patients with MS.

Paresthesias (numbness and tingling), monocular loss of vision, gait problems, weakness, double vision, urinary urgency or frequency, and constipation are typical symptoms. Cognitive dysfunction and fatigue are not uncommon, even in the relapsing stages of disease. Seizures and hearing loss are rare. The EDSS developed by Krutzke in 1983 is the most widely utilized tool used to assess the extent of cumulative neurological compromise. Scores include 0 for normal, 2.0 for minimal disability, 4.0 for increased limitation in walking ability, 5.0 where disability affects daily routine, 6.0 for need for walking assistance, 7.0 for restriction to wheelchair, 9.0 when confined to bed, and 10.0 for demise.

Thus, the clinician making the diagnosis of MS relies on the constellation of clinical signs and symptoms described above, coupled with the neuroimaging features of MS, to make the diagnosis. No single laboratory test is definitive for MS, unlike the case with two other demyelinating disorders discussed in this chapter: positive serum serology for aquaporin 4 antibody (APQ4-Ab) in the case of NMO and positive serum myelin oligodendrocyte antibody in the case of MOG antibody disease (MOGAD). By definition, MS shows negative serum APQ4-Ab and negative serum MOG-Ab. Most MS patients will show the presence of oligoclonal bands (OCBs) in their cerebrospinal fluid (CSF) that represent immunoglobulins produced intrathecally; by definition, to be positive for OCBs, the patient should show two or more unique bands in their CSF that are not present in their serum. These unique immunoglobulins represent the unique production of proteins by inflammatory cells within the central nervous system (CNS). Test methods require collecting CSF by lumbar puncture and analyzing CSF by protein electrophoresis on agarose gel with Coomassie blue staining or an isoelectric focusing/silver staining procedure. Serum must be obtained for comparison.

Clinical diagnosis is challenging, and neurologists have devised a number of algorithms over the years, the history of which is reviewed by Poser and Brinar. In 2001, neuroimaging with MRI resulted in the McDonald criteria, which have been revised several times since, culminating in the 2017 revision. Even with multiple revisions of the McDonald criteria for MS, a significant number of patients continue to receive erroneous clinical diagnoses of MS. This is summarized best by Sand:

“The McDonald criteria for the diagnosis of multiple sclerosis (MS), first introduced in 2001 with revisions in 2005, 2010, and 2017, continue to evolve. The recently published 2017 revisions may facilitate earlier fulfillment of the diagnostic criteria for relapsing-remitting MS. However, confirming a diagnosis of MS is not always straightforward. Clinical heterogeneity along with a lengthy differential diagnosis results in the not infrequent incorrect assignment of a diagnosis of MS. While MS is a common disease, affecting around 900,000 persons in the United States, the astute clinician needs to be aware of alternative diagnoses, such as functional neurologic disorders, migraine, and vascular disease, along with uncommon inflammatory, infectious, and metabolic disorders that may mimic MS. Studies have indicated that, of all new referrals to MS subspecialty centers with a question of MS diagnosis, 30 %–67 % were ultimately determined not to have MS. Regrettably, misdiagnosis and initiation of MS disease-modifying therapy had already occurred in some of these patients. A multicenter case series consisting of patients who had been incorrectly diagnosed with MS11 revealed that over 50 % carried the misdiagnosis for at least 3 years, and more than 5 % were misdiagnosed for over 20 years. In this study, 31 % incurred unnecessary morbidity as a direct result of misdiagnosis. The primary reasons for MS misdiagnosis included inappropriate application of McDonald criteria in syndromes atypical for demyelination or lacking objective clinical findings consistent with MS, and the misinterpretation of or overreliance on MRI abnormalities in the setting of nonspecific neurologic symptoms.”

Thus, the pathologist, neurologist, and neurosurgeon should be aware that the diagnosis of MS might be unclear at various time points during the course of a patient's disease. Contrasting features of MS with other demyelinating disorders discussed in this chapter are provided in Tables 5.1 and 5.2 .

Neurologists and primary physicians encounter patients with MS at multiple time points and all stages of the disease; however, pathologists are seldom involved with making/confirming the diagnosis of MS in patients until the time of demise, i.e., at autopsy. Most, but not all, patients who come to autopsy have met the McDonald criteria for a high likelihood of diagnosis of MS, but usually the diagnosis can be easily confirmed at autopsy due to the near-pathognomonic distribution of lesions and the sharp demarcation of many/most of the demyelinating lesions from surrounding white matter. These features are discussed below in detail since they usually allow for distinction from other rare demyelinating disorders at the time of autopsy.

During early, acute, active phases of the disease, most patients do not come to the attention of either pathologists or neurosurgeons, and biopsy plays no role in the routine diagnosis of MS patients. In other words, the pathologist and neurosurgeon are not involved in the diagnosis of the vast majority of MS patients.

Rarely, a patient will present with or develop acute onset of symptoms during the course of known MS that will prompt neuroimaging work-up. When neuroimaging studies show large enhancing lesions or otherwise unusual features, the clinician may be worried about alternative diagnoses to MS, or even a superimposed second diagnosis such as infection or tumor. Acute/tumefactive demyelinating disease is the label applied to such lesions. Although most examples of acute tumefactive/demyelinating disease prompting biopsy prove ultimately to be the first presentation of MS (i.e., CIS, after sufficient clinical follow-up), this is not true of all examples. Thus, the features of acute/tumefactive demyelinating lesions prompting biopsy are discussed below.

Clinical Features

ADEM is typically a monophasic, acute, inflammatory demyelinating disorder that most commonly occurs in children. Older terms for ADEM included perivenous encephalomyelitis, postinfectious encephalomyelitis, and postvaccinal encephalomyelitis. It was originally described after smallpox vaccinations. The disease was later identified following measles, mumps, rubella, varicella, and vaccinia infections. Today, it usually occurs in children after a nonspecific upper respiratory illness. Onset is usually rapid, with a clinical course that evolves over hours to maximum deficits within days (mean, 4.5 days); there is a wide range in clinical severity of ADEM, but most patients make a full neurological recovery.

Today, ADEM needs first and foremost to be distinguished from MOG antibody disease, also referred to as MOGAD, as discussed below, especially since an ADEM-like presentation is classical for pediatric onset MOGAD (see below). It is estimated that 30 %–50 % of cases initially considered ADEM prove to be MOGAD after serological testing; thus, true ADEM cases, by definition, must be shown to be MOG-negative. Adding to the diagnostic confusion, pediatric ADEM can be the first manifestation of pediatric MS or pediatric NMO/NMOSD.

Clinical manifestations of ADEM are variable. Typically, there is an acute onset of encephalopathy (alteration in consciousness with stupor, lethargy) in association with polyfocal neurologic deficits, sometimes preceded by prodromal symptoms (fever, malaise, irritability, somnolence, headache, nausea, and vomiting). The clinical course of ADEM is usually rapidly progressive, with maximal deficits within 2 to 5 days. Only a minority of children with ADEM (15 %–25 %) require admission to an intensive care unit. Frequent neurologic manifestations include pyramidal signs, ataxia, acute hemiparesis, optic neuritis or other cranial nerve involvement, seizures, spinal cord syndrome, and impairment of speech.

Clinical consensus criteria have been established and revised several times. According to Krupp et al., patients should meet all these features: “A first polyfocal, clinical CNS event with presumed inflammatory demyelinating cause, encephalopathy that cannot be explained by fever, no new clinical and MRI findings emerge 3 months or more after the onset, brain MRI is abnormal during the acute (3 month) phase.” Typically on brain MRI there are “diffuse, poorly demarcated, large (> 1–2 cm) lesions involving predominantly the cerebral white matter, T1 hypointense lesions in the white matter are rare, and deep gray matter lesions (e.g., thalamus or basal ganglia) can be present.” Multiple ( Fig. 5.6A ) and bilateral deep gray matter lesions ( Fig. 5.6B ) are all of the same age and are usually characteristic enough to make the diagnosis without biopsy. Large lesions may be more clinically confusing, and thus, a subset of acute/tumefactive demyelinating lesions prompting biopsy prove to be true ADEM.

While serology results distinguish pediatric ADEM from MOGAD or NMO/NMOSD, clinical and neuroimaging features are required to distinguish ADEM from pediatric MS since specific serological tests do not exist for either ADEM or MS. On neuroimaging studies, ADEM is more likely than MS to involve deep gray matter and show cortical involvement and to show diffuse bilateral lesions, poorly marginated lesions, and large globular lesions on neuroimaging studies. In contrast, a periventricular pattern of lesions, lesions perpendicular to the long axis of the corpus callosum, and black holes on T1 sequences indicative of tissue destruction all favor MS over ADEM. Other imaging features atypical for ADEM include diffuse symmetric brain lesions (which might indicate genetic/metabolic disorders, leukodystrophies or mitochondrial diseases), mesial temporal lesions (that might indicate autoimmune encephalitis), or ischemic lesions with restricted diffusion.

As summarized by Pohl et al., CSF leukocyte count can be normal in 42 %–72 % of children, pleocytosis is typically mild (mostly lymphocytes and monocytes), and CSF protein can be increased, but CSF OCBs are absent. Atypical features on CSF analysis that should prompt consideration of alternate diagnoses include cell count > 50/mm ³ , neutrophilic predominance, or protein > 100 mg/dL.

Due to its low frequency, the category of recurrent ADEM has been eliminated. The definition of multiphasic ADEM has also been revised and is now defined as “two episodes consistent with ADEM separated by 3 months but not followed by any further events. The second ADEM event can involve either new or a reemergence of prior neurologic symptoms, signs and MRI findings.” A percentage of children with relapsing ADEM have other diseases such as NMOSD or MOGAD.

High-dose corticosteroids are currently widely accepted as first-line therapy, and most children make a complete recovery, although children affected less than age 5 years may be left with long-term cognitive deficits. Since fatal examples are very rare, pathologists almost never encounter ADEM at autopsy.

Clinical Features

This disorder is often considered a rare, fulminant form of ADEM, with numerous perivascular hemorrhages as a result of more severe vascular injury, although some debate exists. Both children and adults can be affected. The disease is manifested by an abrupt onset of fever, neck stiffness, seizures, and focal signs. About half the patients have an antecedent upper respiratory tract illness or influenza that occurred 2 to 12 days before onset, similar to ADEM. Because of the fulminant onset, the disease can mimic a direct CNS infection or toxic ingestion. The disease in the past was usually fatal, but in recent years, an increasing number of survivors has been reported, often when treated with therapeutic plasma exchange or intravenous immunoglobulin. Occasional cases will prompt biopsy and, thus, the disease is considered in the differential of acute/tumefactive demyelinating lesions prompting biopsy, especially if hemorrhagic features are present.

Pathologic Features

Grossly, the brain is swollen and edematous and herniations are frequent. The signature pathologic feature is the presence of large areas of white matter damage associated with multiple petechial to larger hemorrhages throughout the cerebral white matter. The extent of hemorrhage is highly variable. Microscopically, “ring and ball” hemorrhages surround necrotic venules, which show fibrinoid vascular necrosis, fibrin exudates, and neutrophilic debris ( Figs. 5.7A–C ). Perivenous demyelination is seen but may be overshadowed by the perivenous hemorrhages.

Clinical Features

NMO, formerly called Devic disease, is an autoimmune demyelinating disorder of the CNS recognized to be a disease distinct and completely separate from MS, with a predilection for the optic nerves and spinal cord. It is far less common than MS. In the past, it was debated whether NMO was a variant of MS or a separate disorder, since involvement of these two sites can occur in both conditions. Complete distinction is now possible since NMO is now defined by clinical, neuroimaging, and laboratory criteria, specifically, the identification of a specific autoantibody response in serum against the astrocyte water channel AQP4 (NMO-IgG). AQP4-seronegative patients are considered to have NMOSD. There have been three published sets of NMOSD criteria (1999, 2006, 2015 International Panel for NMO Diagnosis). Criteria incorporate results of a pathognomonic serum test that detects NMO-IgG. This antibody targets the most abundant water channel protein in the CNS, AQP4-IgG, and on neuroimaging and at pathological examination, lesions are found in anatomic sites with the largest number of astrocytic foot processes. AQP4 is present in the pia and choroid plexus, and the ependymal and histological sections of these areas can show loss of AQP4 with immunostaining and complement deposition, accompanied by microglial activation, in these areas, sites not affected in MS.

The diagnosis of NMO with AQP4-IgG (NMO-AQP4 +) requires one of six core clinical characteristics and a positive serum test for AQP4-IgG. There is no role for CSF testing for the AQP4-Ab since it represents spillover from the serum.

The core clinical presentations are distinguished by their neuroanatomic locations: optic nerve, spinal cord, area postrema (dorsal medulla), diencephalon, brainstem, and cerebrum. Optic neuritis typically presents as acute vision or visual field loss in one or both eyes, whereas transverse myelitis (TM) may present with a variety of motor, sensory, or sphincter problems. TM is commonly (85 % of NMO cases) LETM, defined as involving the spinal cord and spanning the length of three or more vertebral body segments, and involves the central cord with contrast enhancement rather than the lateral cord as does MS. Patients may be wheelchair-bound at the peak of disease. Up to 30 % of patients with NMO TM can show ring enhancement, which, as noted above, serves as the substrate for biopsy of spinal cord acute/tumefactive demyelinating lesion. Optic neuritis is more often bilateral and more often involves the chiasm than in MS; it is often more severe, and complete remission is seen in only about one-third of patients. Visual symptoms usually precede spinal symptoms in NMO, but the reverse is not uncommon.

As outlined by Bennett, brainstem symptoms include ocular motor, motor, sensory, or cerebellar dysfunction associated with parenchymal or ependymal lesions. An area postrema syndrome (incidence: 16 %–43 %) is characterized by intractable hiccups or nausea/vomiting occurring for 7 consecutive days without, or 2 days with, an accompanying MRI lesion in the dorsal medulla. This is often reversible. The predilection for the area postrema is linked to the absence of the blood-brain barrier at this site, allowing access of large molecules such as NMO-IgG.

Diencephalic syndromes include hypersomnolence, narcolepsy, anorexia, hypothermia, hypo-natremia, and behavioral changes due to lesions in the thalamus, hypothalamus, or third ventricular region. Cerebral syndromes include hemiparesis, hemi-sensory loss, encephalopathy, postchiasmal visual field loss, and cortical vision loss due to large, confluent subcortical or deep white matter lesions. Unlike MS, a secondary progressive clinical course is quite rare.

CSF may show GFAP, reflecting the fact that NMO is an astrocytopathy. There is no role for measurement of AQP4-Ab in CSF rather than serum.

Reflecting the presence of lesions in areas with high concentration of APQ4, MRI may show gadolinium enhancement in leptomeningeal and ependymal areas. Contrasting clinical and histological features of MS, ADEM, NMO, and MOGAD are shown in Tables 5.1 and 5.2 .

Pathologic Features

NMO is an astrocytopathy rather than a pure demyelinative disorder, and CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. Histologically, the lesions are more destructive, at least in late stages or severe examples, than those of MS. Early lesions may show relative myelin and axon preservation compared with the severe loss of AQP4, the latter as assessed by immunohistochemistry. NMO lesions often show granulocytes and eosinophils, cell types that are rare in MS lesions. In contrast, MS lesions usually contain lymphocytes.

In NMO lesions, there is a vasocentric deposition of IgG and IgM as well as complement (C9neo) in a rim and rosette pattern, while in at least one subtype of MS, complement is found instead in macrophages. The fact that complement was vasocentric in location lead originally to the suspicion that an antibody was targeting a nearby antigen present in perivascular spaces. It was subsequently shown that this antigen was AQP4, the most abundant water channel present on astrocytic end feet surrounding vessels. Astrocytic end feet are also abundant on the subpial surfaces, and thus NMO lesions are also found in APQ4-rich subpial regions.

In early lesions of NMO there may be prominent eosinophilic ( Fig.5.9A ) and neutrophilic infiltrates and vascular fibrosis, features that are rare in typical MS. In early NMO lesions, AQP loss as assessed by immunohistochemistry precedes astrocyte loss and some reactive astrocytosis can be found within a lesion. However, astrocytic loss precedes myelin loss, underscoring the fact that the astrocyte rather than myelin is the main target in NMO, in contrast to MS. In contrast, a key feature of early MS lesions is reactive astrocytosis with long tapering processes and plump eosinophilic cytoplasm are features that remain throughout early phases of injury. Prior to the demise of astrocytes in NMO, they may demonstrate multinucleation, mitoses, and (rarely) Rosenthal fibers. In NMO, the loss of astrocytes is evidenced by loss of GFAP immunostaining within the lesion, and GFAP + debris can be identified in perivascular macrophages that engulf the dying astrocytic debris. Astrocytes may show blunted processes, differing from the long tapering processes seen in reactive astrocytes that are typical of MS ( Fig. 5.9B ). Macrophages are present, and in subpial, choroid plexus, or ependymal areas with AQP loss, microglial activation may be evident along with loss of AQP immunostaining.

At autopsy, the pathological features of NMO are more readily recognized as being distinctive from MS. In patients dying in early phases of the disease, the cord may be swollen, similar to a tumor, whereas in late stages, there may be considerable shrinkage of the cord and cavitation due to tissue destruction. NMO is histologically characterized by considerably greater loss of axons than is seen in typical MS, along with necrotizing demyelination, cavitation, and focally severe loss of axons in the spinal cord and optic nerves ( Fig. 5.9C ). The tissue involvement often extends over numerous spinal cord segments, paralleling the longitudinally extensive MRI findings. Cavitation in the floor of the third or fourth ventricle may occur ( Fig. 5.9D ). Granulocytes and eosinophils may be seen but can diminish in older lesions. Macrophages are present in older cavitated lesions, and in subpial, choroid plexus or ependymal areas with AQP loss, microglial activation may be evident along with loss of aquaporin immunostaining.

NEUROMYELITIS OPTICA—FACT SHEET

Definition

• n

  Severe, idiopathic inflammatory demyelinating disorder of the spinal cord and optic nerves/chiasm, other sites, associated with AQP4-IgG

Incidence and Location

• n

  Overrepresentation of East Asian and non-white populations worldwide, compared with multiple sclerosis

• n

  Demyelination confined to the CNS

• n

  Lesions occur in areas of strong APQ4 distribution (which is highly concentrated in astrocytic foot processes), including the optic nerve, spinal cord, periependymal sites in the cerebrum and cerebellum including the hypothalamus, third ventricle, corpus callosum, subependymal sites around lateral ventricles, and the floor of the fourth ventricle

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