Acute necrotizing hemorrhagic leukoencephalitis
Acute hemorrhagic leukoencephalitis of Weston Hurst is at the extreme end of the spectrum of demyelinating diseases. It typically follows a viral upper
Mar. 26, 2021
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Balo concentric sclerosis is often thought of as a distinct demyelinating syndrome. The author argues that no absolute evidence differentiates Balo concentric sclerosis from other acute, aggressive forms of multiple sclerosis, although there are many indications that a district pathology may become clear in the future. The article discusses how the spectrum of Balo concentric sclerosis has changed with the discovery of nonfatal cases by MRI. In addition, it describes its spectrum of symptoms and provides the current concepts behind the formation of its rings. The author speculates that much about the mechanism of tissue destruction in multiple sclerosis may be inferred from pathological observations in Balo concentric sclerosis. This update includes the most recent descriptions of MRI findings, comparing Balo concentric sclerosis to prototypic multiple sclerosis.
• Balo concentric sclerosis shares features with other forms of acute demyelination, including multiple sclerosis, neuromyelitis optica, and myelin oligodendrocyte glycoprotein–associated demyelinating disease.
Many cases with a Balo concentric sclerosis pattern noted by magnetic resonance imaging do not progress to multiple sclerosis and have a limited course.
• The concentric ring pattern of Balo concentric sclerosis may be explained by activated microglia and macrophages migrating centrifugally and concentrating in rings for which spacing and activation state is determined by an inhomogeneous diffusion of chemokines and cytokines.
• Activated microglia and macrophages release nitric oxide and oxygen radicals, which may inhibit complex IV of cytochrome c oxidase, leading to failure of energy production and cell death. This might be a hyperacute form of a pathology often associated with multiple sclerosis.
Balo concentric sclerosis is a CNS disease with characteristic pathological and MRI features consisting of alternating concentric rings of demyelinated and relatively myelinated tissues. The evidence that the MRI pattern is tantamount to Balo concentric sclerosis by pathological criteria is based on biopsied cases. The unusual and puzzling pattern has led to a distinctive place in multiple sclerosis nosology following its description by Balό (05). When Balό gave this rare pattern the name “leukoencephalitis periaxialis concentrica,” it became inevitable that future neurologists would link his name to the entity. Nonetheless, the first description of this pathological pattern should be attributed to Marburg who wrote about it 21 years earlier as part of the spectrum of changes found in acute multiple sclerosis (45).
Currently, whether or not Balo concentric sclerosis is a distinct entity is somewhat controversial. A few reviewers have lumped Balo leukoencephalitis periaxialis, Schilder encephalitis periaxialis diffusa, and Marburg encephalitis periaxialis scleroticans under the single term “concentric sclerosis” (16). The distinction between Balo concentric sclerosis, tumefactive multiple sclerosis, and prototypic multiple sclerosis has been described as overlapping syndromes (22). Because about half of the published cases occur in the setting of typical multiple sclerosis (28), Balo concentric sclerosis has frequently been thought to be a variant of multiple sclerosis. Because a significant number of patients with Balo concentric sclerosis lesions have severe and disabling attacks, this view suggests that Balo concentric sclerosis occurs when unfavorable pathological factors are found in a small portion of patients, many of whom progress to multiple sclerosis. Importantly, not all patients with a Balo-like presentation subsequently develop multiple sclerosis.
The pathology of Balo concentric sclerosis was initially described as associated with subacutely progressive fatal demyelinating disease that spared the spinal cord and gray matter (04). Even today, if left untreated, many patients with Balo concentric sclerosis have aggressive disease that can lead to death within the first year. Patients with Balo concentric sclerosis often present with progressive encephalopathy, fever, behavioral changes, cognitive deficits, headache, seizures, increased intracranial pressure, and focal neurologic deficits that most commonly are localized to the supratentorial compartment. A stroke-like onset has been reported (51). The course of Balo concentric sclerosis may be monophasic, relapsing, or progressive. A picture reminiscent of Devic syndrome has been observed in association Balo concentric sclerosis pathological changes in the spinal cord (26; 01; 35) and rarely optic nerves (24; 50). Balo concentric sclerosis lesions also have been described in the brainstem (19).
After the introduction of MRI, Balo concentric sclerosis was additionally diagnosed in patients with a benign course. The first diagnosis of Balo concentric sclerosis by MRI occurred in 1986 (17), and since then over 100 cases have been reported. Rarely, MRI changes in Balo concentric sclerosis can be seen with little clinical symptomatology. For this summary, the author reviewed 65 cases reported by MRI between 1993 and 2009 (21; 59; 66; 18; 39; 13; 14; 12; 67; 60; 33; 52; 62; Ng S-H et al 1999; 44; 09; 11; 27; 49; 28; 20; 57; 02; 69; 30; 40; 51; 10). Asians were overrepresented in these reports. Genders were represented nearly equally (55% women), and the average age of disease onset was 34 years, ranging from 4 to 59 years. The clinical courses were variable, and the impact of treatment was not clear. During the acute stage of disease, some patients received corticosteroids, immunosuppressants, plasmapheresis, or intravenous immunoglobulin. Chronic treatments included disease-modifying therapies conventionally used in multiple sclerosis, azathioprine, and mitoxantrone. Some patients were either not treated or treatment was not reported. In addition to case studies, a series of Balo concentric sclerosis patients were examined for the presence or absence of many key findings described in prototypic multiple sclerosis using 7T MRI, with the investigators concluding that considerable overlap exists (06).
Prior to the institution of MRI, Balo concentric sclerosis was largely diagnosed by a clinical signature of a subacute, monophasic illness that led to death. Subsequently, the course has been shown to be much more benign. Of reported cases reviewed by the author, approximately 14% died, were severely disabled, or were progressing and severely affected at the time of report. About 19% of patients developed a course compatible with relapsing-remitting multiple sclerosis; about 3% could have been diagnosed with Devic disease; 26% were followed for longer than 2 years and had displayed no future clinical activity (possible monophasic course); and 38% were stable but had been followed for less than 2 years (most for 1 year or less). This sample is likely too small to draw strong conclusions, but fits within the spectrum of clinical outcomes reported for tumefactive multiple sclerosis (31; 41).
In a relatively large series of Balo concentric sclerosis, a benign long-term course was seen despite the presence of additional MRI changes that were consistent with multiple sclerosis (10). In this series of 7 Chinese patients, 5 had both Balo concentric sclerosis and classical multiple sclerosis lesions by MRI, but only 3 patients relapsed during a follow-up period of 4 to 13.5 years. Some observations suggest a milder course of Balo in rare pediatric cases, perhaps due to maturational differences in the immune system or brain (38). A 7T MRI study revealed that intralesional veins tend to be found, along with other characteristics shared with prototypical multiple sclerosis. However, distinctly found among the Balo group were the absence of cortical and U fiber lesions and the presence of microhemorrhages in some lesions.
Case 1. A 42-year-old European-American woman developed gradual weakness and incoordination of her left arm and leg in November 2003. A brain MRI scan lead to a stereotaxic brain biopsy that was read as consistent with Balo concentric sclerosis.
The patient was treated with intravenous immunoglobulin but did not improve. After a brief consultation at the Multiple Sclerosis Center, she was managed with interferon-beta-1a subcutaneously 3 times a week and oral azathioprine. In January 2006, she again was seen at the Multiple Sclerosis Center. She had been clinically stable except for 1 episode compatible with benign paroxysmal positional vertigo in 2005. A follow-up MRI scan performed in September 2006 revealed that her Balo concentric sclerosis lesion had transformed into a large non-enhancing area of T2-signal abnormality without rings.
No new lesions were identified. This author believes that this case is consistent with the phenotype that is currently very common.
Case 2. A 3-year and 11-month-old African-American girl awoke crying in March 2003. She then developed a flaccid paralysis of the left arm and leg over several hours. While being evaluated in the emergency department, she had a focal seizure involving the left arm. A T2-weighted MRI scan showed a large, right occipital lesion that involved the splenium and enhanced strongly in its periphery. A biopsy of the lesion revealed demyelination. A lumbar puncture showed no abnormality of cells, a normal IgG index, and no oligoclonal bands. The patient was well until July 2003 when she developed right facial twitching. The following day the patient’s right face was weak, and her speech was slurred. She was admitted to the hospital where an MRI scan showed a new large left parietal lesion consistent with Balo concentric sclerosis.
Thereafter, she had multiple severe exacerbations followed by a progressive course that resulted in quadriparesis and dementia. In October 2005, studies sent to Jefferson Medical College in Philadelphia, Pennsylvania were compatible with a diagnosis of metachromatic leukodystrophy. Leukocyte DNA analysis showed no copies of the common pseudodeficiency allele or late infantile mutation, and she was felt to be heterozygous for the common adult mutation. Subsequently, the patient was lost to follow-up. The author believes case 2 represents an unusual coincidence of idiopathic inflammatory demyelinative disease in the setting of abnormal myelin that lead to MRI changes of Balo concentric sclerosis and an aggressive form of disease (29; 55).
Whether there are etiologic differences between Balo concentric sclerosis and other idiopathic inflammatory demyelinating diseases is unknown. In the author’s opinion, Balo concentric sclerosis is best thought of as a descriptive pathological and radiological term. The author speculates that Balo concentric sclerosis is an uncommon subgroup of tumefactive multiple sclerosis. (See also MedLink Neurology clinical summary, Tumefactive multiple sclerosis.) Whether there is a unique immunological basis for the Balo concentric sclerosis pattern has been poorly investigated.
Macroscopically, Balo concentric sclerosis lesions are composed of areas of myelin preservation alternating with zones of myelin destruction (70). In areas of myelin loss, oligodendrocytes are depleted and axons are transected. In the central core of the lesion, myelin is generally preserved. Usually, the outer border of the demyelinated region is sharp, but its inner margin is not well defined (40). Findings on 7T MRI scanning suggest that proximity to blood vessels may play a role in supporting the concept of early vascular pathology causing “ischemic preconditioning” as a necessary step in ring formation (07; 22). In favor of a multiphasic evolution of pathology, an early ischemic phase in lesion development was suggested by magnetic resonance spectroscopy (MRS) in a single case study (54). There was a transiently elevated lactate peak (typically seen in ischemic stress), and this was followed 6 weeks later by an elevated lipid peak, corresponding to proposed demyelination.
The microscopic picture of Balo concentric sclerosis is thought to be consistent with the multiple sclerosis pathological subtype described as type III (64), in which oligodendrocytes are primary targets (36). Although classification of multiple sclerosis into 4 distinct, persistent, pathological patterns is controversial, type III pathology has been felt to result from damage to oligodendrocytes by oxidative stress. Upregulation of inducible nitric oxide synthase in macrophages and microglia occurs within demyelinated bands, and upregulation of protective proteins such as hypoxia inducible factor (HIF-1 alpha) and heat shock protein 70 (HSP-70) are found in oligodendroglia and other glial cells at the edge of actively demyelinating lesions and within the preserved regions of myelin (64). These findings have been used to explain the pattern of concentric bands. In areas of preserved myelin, astrocytic proliferation has been described (40).
Studies combining immunohistochemistry, electron microscopy, and quantitative microscopy in multiple sclerosis have suggested that microglia and macrophages damage myelin and axons by releasing nitric oxide and oxygen radicals, which functionally inhibit the main catalytic subunit of complex IV, cytochrome c oxidase-1 (COX-1), in mitochondria. This has been hypothesized to lead to loss of mitochondrial energy production, which could easily compromise cellular hemostasis, resulting in tissue loss (43). In Balo concentric sclerosis, as well as in multiple sclerosis, defects of mitochondrial respiratory chain complex IV are present in demyelinated lesions involving oligodendrocytes, astrocytes, and axons, but not involving microglia (42). One theoretical mechanism for the pattern of bands of myelin that are alternately preserved and destroyed is that tissue destruction induced by COX-1 inhibition results in a counter-regulatory elaboration of protective proteins such as HIF-1 alpha and HSP-70 in the oligodendrocytes of neighboring tissues. In the areas with high HIF-1 alpha and HSP-70 concentration, inflammatory infiltrates of microglia and macrophages may be tolerated until they migrate to another region. In an area without a sufficient concentration of protective proteins, demyelination could occur again, resulting in an alternating, concentric pattern (64).
A slightly different explanation for the pattern of alternating demyelinated and myelinated rings postulates uses a mathematical model based on nonlinear chemotaxis of effector monocytes and microglia with a resulting variable density of damaged oligodendrocytes (32). The proposed model postulates that if the flux of 1 diffusing substance is dependent on the gradient of another, an inhomogeneous distribution of attracting and modifying substances (such as chemokines and cytokines--not specified by the model) would occur. This would control the speed and concentration of activated macrophages and microglia across the area of disease involvement. Areas that become demyelinated would have a high concentration of effector cells whereas preserved areas would demonstrate a low concentration. The production of chemokines and cytokines by migrating cells themselves might accentuate this inhomogeneity, attracting more cells to areas where cells existed in high concentrations.
In contrast to the conventional notion of early CD4+ T-cell involvement in demyelinating lesions, observations that microglia and macrophages are the earliest cell infiltrates into areas of damaged myelin have been published (23). The parallels between the pathological changes described above for Balo concentric sclerosis and those found in areas of early destruction and active inflammation in multiple sclerosis make it is easy to speculate that Balo concentric sclerosis is a model for immune-mediated tissue destruction in multiple sclerosis. The etiology of the earliest lesion in multiple sclerosis is as yet unknown.
One theory concerning the initial pathological events in Balo concentric sclerosis postulates that there is an antibody-mediated astrocytopathy involving loss of aquaporin-4 and connexins (34; 47). Oligodendrocyte injury mediated by the above inflammatory mechanisms then follows during an antibody-independent event (in favor of a degenerative secondary phase).
An extensive review of cerebrospinal fluid examinations in a large cohort of Balo concentric sclerosis patients revealed unlike prototypical multiple sclerosis, approximately 2 out of 3 of patients were negative for oligoclonal bands and for elevation of IgG synthesis (25). Pleocytosis was a more common finding among Balo patients versus multiple sclerosis. Oligoclonal bands among Balo patients were frequently transient. The investigators suggest that Balo concentric sclerosis pathology is more similar to neuromyelitis optica and MOG-related demyelination than to multiple sclerosis.
Balo concentric sclerosis is possibly more common in Asian than in Caucasian populations (58; 65; 12). The clinical manifestations in these 2 groups appear similar.
No proven strategy for prevention of Balo concentric sclerosis is known.
The most likely clinical diagnoses in a patient with Balo concentric sclerosis changes are demyelinating processes, including acute disseminated encephalomyelopathy; acute multiple sclerosis, Marburg variant; tumefactive multiple sclerosis; atypical Devic syndrome (the presence of aquaporin-4 antibody plus large cerebral lesions); lymphoma; glioma; metastatic cancer; and abscess. The pathophysiological distinctions among the demyelinating conditions listed above are only partially known. A consensus conference providing a detailed differential diagnosis of multiple sclerosis (48) can be used to generate other alternative diagnoses, which vary with the region of the central nervous system that is involved.
Other defined illnesses have been reported uncommonly in association with a Balo concentric sclerosis MRI pattern, including progressive multifocal leukoencephalopathy (46; 29) and human herpes virus 6 encephalitis (56); see clinical vignette, Case 2. Balo concentric sclerosis MRI patterns may coexist with classical multiple sclerosis lesions (27; 49; 63; 41) and in people with Devic syndrome (19). Balo concentric sclerosis has been reported in a case of CADASIL and in rare cases of neuromyelitis optica (34; 15).
Although the diagnosis of Balo concentric sclerosis is usually first considered based on a characteristic MRI pattern, published cases demonstrate variability in what has been accepted as being suggestive of Balo concentric sclerosis lesions. Evolution of Balo concentric sclerosis lesions into a homogeneous or granular appearance may account for part of this variability. Case reports have illustrated MR images demonstrating 6 or more thin concentric bands or exhibiting only 1 or 2 thick bands. Some cases are undoubtedly reported as tumefactive multiple sclerosis (61). The lesions may be multiple or single and vary in size from less than a centimeter to lesions that involve most of the supratentorial white matter (18). The MRI evolution of Balo concentric sclerosis rings takes at least 2 distinct patterns. Chen and colleagues reported that bands spread centripetally, with new bands forming around established bands (12). Others (60; 28) have argued that all rings emerge simultaneously. One particularly illustrative case demonstrated the slow evolution of a centrifugal pattern of concentric alternating bands over 57 days using 4 sequential MRIs (35). The chronic time course of Balo concentric sclerosis appears to vary. Serial scans have shown regression of lesions, with conversion to homogeneous signals (28), prolonged maintenance of the rings, (Ng et al 1999), and complete disappearance of the rings (10). 7T MRI scanning in a single patient has suggested possible superiority versus 1.5T MRI in imaging the rings (07). A small series of patients with Balo concentric sclerosis were examined for the presence or absence of many key findings described in prototypic multiple sclerosis using 7T MRI (Behrens et at 2018). The investigators concluded that some findings were frequently present in both syndromes, suggesting a common pathophysiology (a central vein sign, Dawson fingers), and there was a suggestion that juxtacortical lesions and cortical involvement was perhaps absent in Balo concentric sclerosis, as distinct from multiple sclerosis.
Balo concentric sclerosis frequently occurs without associated cerebrospinal fluid oligoclonal bands or evidence of temporal and spatial diversity. The finding of oligoclonal bands seems to be associated with recurrent attacks. In general, visual evoked potentials are normal, although prolonged P100s do not exclude the diagnosis.
Although biopsies have often been performed to confirm a demyelinating etiology or to exclude tumor or infection, this is usually unnecessary. The use of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography may be helpful in excluding hypermetabolic lymphomas and high-grade gliomas from the differential diagnoses as demyelinating lesions are usually hypometabolic (68).
Most acute attacks of Balo concentric sclerosis have been treated with corticosteroids, but the results of such therapy are anecdotal (class IV evidence only). Although acute attacks of Balo concentric sclerosis possibly respond to corticosteroids, if these are ineffective, plasma exchange may possibly be beneficial, or at least seems reasonable based on experience with other severe bouts of demyelinating disease.
The acute attack of Balo concentric sclerosis may be isolated, may be followed by a relapsing-remitting course, or may lead to a progressive and potentially fatal outcome. This variability makes the choice of treatment following the acute attack problematic. Those individuals with isolated attacks or long periods of clinical quiescence may not need chronic therapy.
Patients with the most aggressive courses generally die within the first year of illness. As more aggressive therapies become available for the treatment of immune-mediated diseases of the CNS, it is possible that death and severe disability will be a less frequent outcome. An example of an aggressive course is that of a 16-year-old boy who responded partially to intravenous corticosteroid but worsened once treatment was withdrawn (39). He improved after administration of intravenous cyclophosphamide and ACTH and was then clinically stable for a 2-year period while taking azathioprine. Clinical stability was reported in a single case of plasma exchange followed by natalizumab (07). A single patient with aggressive disease seemed to respond poorly to steroids and plasma exchange followed by cyclophosphamide and alemtuzumab, supporting the concept that in some patients the inflammatory lesions of Balo concentric sclerosis are independent of lymphocyte mediated processes (08).
The author is not aware of long-term data systematically studying any therapy. Until this is possible, treatment must be based on the presence of progression, the likelihood of recurrent attacks, and the severity of the first attack. Reviewing MRI scans carefully for multiple sclerosis-like lesions in the brain and spinal cord, restudying patients with MRI for new areas of demyelination, and performing lumbar punctures for the presence of oligoclonal bands, especially several months after the initial attack, may provide insight into the likelihood of recurrent or progressive disease. Visual-evoked potentials and aquaporin-4 antibodies may also be helpful in selected cases. From the author’s review of published cases, multiple large Balo concentric sclerosis lesions possibly portend a worse prognosis and may indicate patients for whom aggressive therapy should be instituted. If the course of Balo concentric sclerosis is similar to tumefactive multiple sclerosis, then chronic treatment seems reasonable (37; 03).
A successful pregnancy has been reported in a 23-year-old woman diagnosed as having Balo concentric sclerosis on the basis of a rather atypical MRI scan and a remarkably elevated spinal fluid protein (02).
Thomas Scott MD
Dr. Scott of Allegheny Neurological Associates has no relevant financial relationships to disclose.See Profile
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Mallinckrodt, Mylan, Serono, and Teva-Marion for service on advisory boards and as a consultant, and stock options from NKMax America for advisory work.See Profile
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