Acute disseminated encephalomyelitis and acute haemorrhagic necrotizing leukoencephalitis

Acute disseminated encephalomyelitis (ADEM) and acute haemorrhagic necrotizing leukoencephalitis (AHL or Hurst syndrome) are monophasic diseases, which most commonly affect children or young adults. The patients present with multifocal neurological symptoms often associated with a disturbed consciousness [35, 59, 78]. Recurrent disease courses have been suggested in single patients, making a clinical differentiation between ADEM and MS difficult [22, 76]. The clinical outcome of ADEM is typically favourable in contrast to its fulminant variant, Hurst syndrome. The pathophysiology of these diseases is unknown. An autoimmune response to a CNS antigen triggered by infection or vaccination has been discussed as the underlying disease mechanism, since ADEM and Hurst syndrome are often (but not always) associated with preceding infections of the upper respiratory tract or vaccinations [41, 71].

Histologically, ADEM is characterized by small perivascular demyelinating lesions (Fig. 2a), which may be confluent. The perivascular demyelinating “rim” is infiltrated by numerous foamy macrophages and a few lymphocytes (CD3- and CD8-positive T cells, B cells and plasma cells) (Fig. 2b). In general, demyelination is—in contrast to MS lesions—limited to perivascular areas with inflammatory infiltrates. Thus, in brain biopsies profound inflammation in the white matter, which is associated with perivascular demyelination only, is suggestive of ADEM. Having said this, however, it is nevertheless true that essentially similar tissue alterations can be seen in the vicinity of active MS lesions. It is therefore frequently not possible to definitely distinguish between ADEM and MS, in particular when only small biopsy specimens are available.

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Fig. 2

Different demyelinating diseases. ADEM is characterized by very limited perivascular demyelination [LFB-PAS; (a)] and perivascular infiltrates that consist mostly of foamy macrophages [immunohistochemistry for KiM1P; (b)]. In vanishing white matter, a diffuse loss of myelin is observed [LFB-PAS; (c)]. The number of oligodendrocytes in affected white matter areas is markedly reduced [immunohistochemistry for CNPase (d)]. In contrast to early MS lesions, the demyelinated lesions are infiltrated by relatively few macrophages [immunohistochemistry for KiM1P; (e)]. In X-linked adrenoleukodystrophy, numerous bizarre astrocytes can be found within the lesions (arrows in f) as well as lymphocytic perivascular infiltrates (arrowhead in f; haematoxylin and eosin staining). The lesion areas are completely demyelinated (g) and in macrophages needle-like inclusions may be found (insert in g). In Alexander’s disease large CNS areas with an almost complete loss of myelin are found [immunohistochemistry for MBP; (h)]. The histopathological characteristic of Alexander’s disease is numerous GFAP-positive Rosenthal fibres [immunohistochemistry for GFAP; (i)]

Hurst syndrome displays circular haemorrhages and fibrin deposits around smaller often necrotic vessels together with infiltrates consisting of neutrophils, lymphocytes and macrophages. Among the inflammatory cells, neutrophils are the dominant cell population. Similar to ADEM, the loss of myelin is limited to the area of inflammation. Frequently, the axon cylinders are severely affected resulting in necrotic foci rather than real demyelination [1, 34].

Central pontine myelinolysis

In 1959, Adams described for the first time a disease characterized by demyelinating symmetrically located central pontine lesions and therefore named it central pontine myelinolysis [2]. Subsequent studies revealed that such demyelinating lesions are not confined to the pons, but can be found in other regions of the brain that show a strong admixture of grey and white matter such as cerebellum or the extreme and external capsule [31, 64]. Central pontine myelinolysis (CPM) is a rare disease associated with conditions such as alcoholism, chronic malnutrition, cirrhotic liver disease and transplantation. CPM has been related to a rapid rise of serum sodium from a hyponatremic baseline and similar demyelinating lesions have been found experimentally such as electrolyte-induced myelinolysis in rats [44, 45, 62].

Histopathologically, these lesions are characterized by extensive, sharply demarcated demyelinating lesions. Oligodendrocytes are completely eliminated. The extent of axonal damage varies between patients [30]; older lesions may display cystic (necrotic) cavitations in the centre of the demyelinating lesion [60]. Neurons are well preserved. Within the lesions, numerous macrophages are observed. The number of macrophages as well as the presence of LFB-positive myelin degradation products within the cytoplasm of macrophages depends on the age of the lesion. In contrast to MS lesions, lymphocytic infiltrates are rare. In general, the diagnosis of CPM can be easily made due to the typical distribution of the lesions. Even in rare instances when extrapontine lesions are not accompanied by pontine lesions [31, 64], the lack of lymphocytic infiltrates in CPM lesions makes confusion with early MS unlikely.

A second demyelinating condition observed almost exclusively in alcoholics is Marchiafava-Bignami (MFB) disease. In MFB disease, lesions are mostly located in the corpus callosum, but they may also be found in the optic chiasm, anterior commissure and cortex [38]. The histopathological characteristics are very similar to the changes observed in CPM, indicating that these two conditions may share some pathogenic mechanisms. However, MFB and CPM are rarely observed in the same patient [29].

Vanishing white matter disease

Vanishing white matter (VWM) disease, also called myelinopathia centralis diffusa or childhood ataxia with diffuse central hypomyelination, has only recently been recognized as a disease entity caused by mutations in the EIF2B1 gene family [49, 86]. In the majority of cases, the disease begins neonatally or in early childhood after infections with fever or mild head injuries with an episodic or progressive neurological deterioration. The neurological symptoms include cerebellar ataxia, spasticity, optic atrophy and epilepsy. In addition to disease onset in childhood, adult cases are also described [12, 27, 73]. MRI reveals diffuse signal abnormalities and cystic changes in the cerebral white matter [73, 84, 85]. Due to its neurological characteristics, early disease onset and extensive MRI abnormalities, the disease would only rarely be considered as a differential diagnosis to MS in children. However, in adults the diagnosis of the disease may be difficult. Histopathologically, the disease is characterized by a widespread, diffuse loss of myelin and oligodendrocytes (Fig. 2c, d), accompanied by a significant reduction in axons, characteristics also found in MS lesions [17, 74, 88, 91]. In contrast to early MS lesions, only a moderate infiltration with macrophages/microglia is observed and T and B cells are absent (Fig. 2e) [15]. Although only moderate numbers of macrophages/microglial cells are seen in VWM disease, single macrophages containing myelin degradation products, such as MAG, CNP, etc. within their cytoplasm may be present in some VWM lesions, indicating an active ongoing demyelinating process. In the normal appearing white matter, the number of oligodendrocytes is significantly increased [15, 74]. A substantial number of oligodendrocytes display the morphological characteristics of apoptosis and express apoptosis-related proteins indicating that oligodendroglial cell loss is an early feature in the disease process [15, 88].

Adrenoleukodystrophy

X-linked adrenoleukodystrophy is characterized by adrenal insufficiency and CNS abnormalities. The disease is caused by mutations in the ABCD1 gene leading to the accumulation of very long chain fatty acids (VLCFA) [58]. In the majority of patients, the disease starts in the first or third/fourth decade; only in a subset of patients is the brain affected (cerebral variant of ALD) [57]. Measurement of VLCFA in plasma is the key diagnostic technique and mutation analysis will confirm the suspected diagnosis. Biopsies are needed only in exceptional situations, e.g. in patients in whom the diagnosis is unexpected due to an atypical clinical course. Histologically, cerebral ALD shares many features with MS lesions. Like MS lesions, they are characterized by demyelination, relative loss of axons and inflammation (Fig. 2f). Within the lesions, a diffuse loss of myelin proteins (MBP, CNP, MOG, MAG, PLP) is observed (Fig. 2g) and no sharp border between the lesions and the “normal appearing” white matter can be defined, similar to pattern III MS lesions. The number of oligodendrocytes is reduced within the lesion compared to the NAWM, but we observed only a few oligodendrocytes with an apoptotic or pycnotic morphology, similar to observations described by Ito et al. [36]. The number of axons is reduced and axonal spheroids can be observed. The perivascular and parenchymal infiltrates are composed of CD3- and CD8-positive T cells, plasma cells as well as macrophages, which may contain myelin degradation products within their cytoplasm. We did not see a deposition of complement in macrophages or on myelin, but this has been reported for a subset of patients in an earlier study [72]. Reactive and bizarrely formed astrocytes are scattered through the lesion (Fig. 2f). They are characterized by large, plump cell bodies resembling large gemistocytes. The detection of needle-like inclusions within macrophages is typical for ALD (insert in Fig. 2g). These inclusions can most readily be detected in the Luxol-Fast-Blue/PAS staining where they appear as small, colourless cavities.

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is caused by a persistent measles virus infection. The onset of the disease, that affects mostly children, is insidious, and the outcome often fatal. With the introduction of measles vaccination, the incidence of SSPE has significantly decreased.

First, pathologic changes are observed in the white matter of the hemisphere [63]. The histopathological changes are relatively unspecific: widespread, but focal perivascular infiltrates in the white and grey matter associated with astrocytic proliferation as well as microglial nodules. These inflammatory reactions are accompanied by diffuse demyelination (Fig. 3c), which can be very limited in early disease stages. In neuronal or oligodendroglial nuclei, specific inclusions may be found, the so-called Cowdry type A inclusion bodies. The detection of measles virus antigen by immunohistochemistry leads to the definitive diagnosis of SSPE (Fig. 3d, e) [20].

Encephalitis without demyelination

Encephalitis may present with multifocal lesions in the grey and white matter and is therefore the basis for a possible diagnosis of multiple sclerosis in certain circumstances. Encephalitis without demyelination is most frequently caused by infectious pathogens or an autoimmune process.

Among the infectious pathogens, viral infections are the most important cause of encephalitis without demyelination. Necrotizing viral encephalitis, such as herpes, CMV or VZV, is easy to diagnose; the detection of the virus by immunohistochemistry permits the definitive diagnosis. Unfortunately, there are numerous additional viruses, which may cause encephalitis, but are more difficult to identify. Arboviruses (West Nile virus, Japanese encephalitis, St Louis encephalitis, Western and Eastern equine encephalitis, Central European tick-born encephalitis) and enteroviruses (echovirus, coxsackievirus) are some known examples that infect the CNS and result in encephalitis and/or meningitis. Viral encephalitis affects predominately the cortex. The histological characteristics consist of perivascular and parenchymal infiltrates (lymphocytes, macrophages, microglia; Fig. 3g), microglial nodules as well as dying nerve cells surrounded by microglial cells (neuronophagia; Fig. 3f). Neurons and granzyme B expressing CD8-positive T can be found in close proximity, suggesting a direct cytotoxic effect of CD8 T cells on neurons.

Autoimmune processes are a further cause for encephalitis without demyelination. In a subset of patients, autoimmune-mediated encephalitis is associated with malignancies (also called paraneoplastic encephalopathy or paraneoplastic encephalitis). Limbic encephalitis is the most frequent autoimmune encephalitis with 120 cases described in the literature (for review see [89]. Clinically, it is characterized by short-term memory impairment, temporal lobe seizures and psychiatric symptoms. The typical MRI findings consist of signal abnormalities in the mesial temporal lobes without contrast enhancement [10, 89]. In CSF and/or serum, autoantibodies to neuronal antigens (e.g. Voltage-gated potassium channels or intraneuronal antigens (such as anti-Hu, anti-Ma2)) [10] can be detected in the majority of patients. However, the pathogenesis of autoimmune encephalitis is still a matter of debate; autoantibody-mediated neuronal cell lysis as well as cellular immune mechanisms are discussed [3, 4, 70]. The histological CNS changes in patients with autoimmune encephalitis consist of perivascular T and B cell infiltrates, microglial activation, microglial nodules and gliosis [19, 90]. Rasmussen encephalitis is another rare syndrome in which an autoimmune reaction is the suspected underlying cause of the disease. It affects predominately children, but it can in rare instances also be seen in adults. It is characterized by a progressive destruction of one hemisphere. In early disease phases, the pathological changes consisting of focal and/or perivascular inflammatory infiltrates (with a prominent number of CD8 positive T cells), microglia activation, astrocytosis and single neuronophagia are limited to the superficial and deep cortical layers. Cytotoxic T cells are seen in close association with cortical neurons, suggesting a T cell-mediated mechanism of tissue injury [13]. In addition, profound loss and acute destruction of astrocytes is a characteristic feature of active lesions. In contrast, in late disease phases, extensive destruction with vacuolation of all cortical layers, massive loss of neurons and a prominent astrocytosis were found, while the lymphocytic infiltration was minimal or absent [13]. The subcortical white matter may be affected as well, displaying a diffuse pallor of myelin, loss of axons, foci of lymphocytic infiltrates and reactive astrocytic changes [11, 69].

Vasculitis

CNS vasculitis is a heterogeneous disease group, which represents either isolated vasculitis of the CNS or is part of a systemic vasculitis, such as Wegner’s granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa or collagenoses associated with vasculitis (for review, see [37, 92].

CNS vasculitis mostly affects small- and medium-sized vessels. The histological hallmarks of CNS vasculitis are infiltration of the vessel wall with inflammatory cells (Fig. 4a) and a fibrinoid necrosis of the vessel wall. The inflammatory destruction of the vessels (Fig. 4b) results in thrombosis of the vessels causing strokes or haemorrhages. The inflammation within the vessel wall consists of macrophages, T cells and B cells, and occasionally giant cells are found as well. The vasculitis may be accompanied by mild to severe inflammatory infiltrates in the CNS parenchyma making the differentiation between MS and vasculitis occasionally difficult in the absence of a fibrinoid necrosis of the vessel walls or thrombotic vessels. In contrast to MS, no demyelination is observed.

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Fig. 4

In vasculitis, the infiltrates are localized within the vessel wall and consist mostly of T cells [immunohistochemistry for the T cell marker CD3; (a)]. Frequently, the vessel wall is destroyed [reticulin staining; (b)]. Noncaseating granulomas consisting of multinucleated giant cells and epitheloid cells surrounded by a lymphocytic wall are the histological hallmarks of neurosarcoidosis (c). In CNS lymphomas, a perivascular accumulation of neoplastic B cells is characteristic [haematoxylin and eosin; (d)]. The high proliferation index in lymphomas may help to distinguish lymphomas from vasculitis or viral encephalitis. However, occasionally also cases of vasculitis and encephalitis show a marked proliferation. The detection of a monoclonal B cell population by PCR confirms the suspected diagnosis of a B cell lymphoma [immunohistochemistry for the proliferation marker Ki67; (e)]

Sarcoidosis

Sarcoidosis is a chronic relapsing inflammatory disease of unknown aetiology with variable clinical manifestations; the most common presentation of sarcoidosis is pulmonary involvement. The CNS is affected in 5–25 % of the patients [39, 55, 81]. Cranial MRI reveals the predilection of neurosarcoidosis for the leptomeninges and basal midline structures such as hypothalamus, optic chiasm and the pituitary gland, but also multiple hyperintense parenchymal and periventricular lesions are observed, which may be indistinguishable from MS lesions [56, 65, 83]. In the absence of a systemic disease, pathological evaluation of one of the CNS lesions is the only way to establish the diagnosis of neurosarcoidosis.

Histopathologically, neurosarcoidosis is characterized by non-caseating granulomas consisting of epitheloid histiocytes, lymphocytes, plasma cells and multinucleated giant cells (Fig. 4c). The nuclei in the giant cells are either arranged along the cell border or are randomly clustered in the cytoplasm. In rare instances, necrotizing granulomas can be found in patients with neurosarcoidosis [65]. Ziehl-Neelsen and auramine-rhodamine stainings (mycobactria), silver impregnation techniques (fungi) and examination with polarized light help to distinguish neurosarcoidosis from other granulomatous diseases such as tuberculosis, fungal infections (e.g. histoplasmosis, aspergillosis, cryptococcosis) or foreign body type granulomatous inflammation.

Lymphoma

Primary B cell lymphomas of the CNS (PCNSL) are relatively rare; they account for less than 1% of CNS tumours. Although lymphomas and MS lesions may cause similar MRI changes [52, 66], these two entities can be distinguished easily by histology. B cell lymphomas are easy to diagnose due to their high cellularity, angiocentric growth pattern (Fig. 4d), typical morphology, high proliferation (Fig. 4e), and immunopositivity for B cell markers. However, treatment of patients with steroids prior to biopsy may obscure the diagnosis of lymphoma. Treatment with steroids may lead to the almost complete elimination of the neoplastic B cell population resulting in astrogliosis and perivascular T cell infiltrates resembling vasculitis or encephalitic diseases [28]. Occasionally, B cell lymphomas are preceded by demyelinating lesions, undistinguishable from MS lesions, as described in detail above [5, 14, 47, 48].

A rare variant of PCNSL is the lymphomatosis cerebri that in contrast to the typical PCNSL does not form a cohesive mass, but infiltrates into the CNS diffusely and widely [9, 75]. The patients typically present with rapidly progressive dementia. As a result of the diffuse infiltration of lymphomatosis cerebri, MRI findings may mimic other white matter disorders, such as Binswanger disease, leukoencephalopathy, viral infection or infiltrating glioma [21, 26, 82]. Histopathologically, lymphomatosis cerebri is characterized by the infiltration of the white matter with individual CD20-positive lymphoid lymphoma cells without forming mass lesions [9, 42, 75]. Modest numbers of lymphoma cells together with reactive T cells can be found perivascularly. These histopathological changes may be associated with subtle myelin pallor. One case report describes the presence of focal necrosis [9].

It may be especially challenging to differentiate T cell lymphomas of the CNS from inflammatory entities, such as vasculitis. In a large series of PCNSL (n = 370), T cell origin has been described in 2% of the cases [24]. Primary T cell lymphomas of the CNS frequently show an angiocentric growth pattern. The morphology of the neoplastic T cells has been described as small, medium to large or pleomorphic [33, 79]. Parenchymal necroses as well as necrotic vessels may be present. Immunohistochemically, the neoplastic cells express CD3 as well as CD8 and perforin or granzyme B [33]. Proliferation is usually prominent. The detection of a clonal T cell receptor gene rearrangement by PCR helps to establish the diagnosis of a T cell lymphoma [33].

Other CNS tumours

Since early MS lesions are characterized by hypercellularity as well as extensive and prominent astrocytosis, they might be confused with astrocytic tumours, especially in small biopsy specimens. Furthermore, reactive astrocytes in MS lesions often display a marked pleomorphism and even astrocytes, with atypical mitotic figures (Creutzfeldt-Peters cells) being observed in MS lesions. Therefore, low-grade astrocytomas, especially those with a prominent gemistocytic component may lead to confusion in the differential diagnosis of demyelinating lesions.

The hypercellularity observed in early MS lesions is at least partly caused by macrophages. Cytologically, macrophages may resemble neoplastic oligodendrocytes. However, while neoplastic oligodendrocytes often have a clear cytoplasm as an artificial reaction to the embedding process, macrophages display a foamy and granular cytoplasm. The presence of demyelination and relative axonal preservation together with stainings identifying macrophages (e.g. CD68, KiM1P) will help to avoid misdiagnosis. Review of the clinical and radiological findings will further help towards a correct diagnosis.

This study was supported by the research program from the Faculty of Medicine, Georg-August-University Göttingen, the Hertie Foundation and 6th Framework of the European Union, NeuroproMiSe, LSHM-CT-2005-018637. We thank our colleagues from the Departments of Neuropathology from Bremen, Erlangen/Nürnberg, Ulm, Mainz, Greifswald, Department of Pathology and Dermatopathology, Diagnostic Centre, Berlin, the Montreal Neurological Institute, Montreal, Canada as well as our colleagues from the Department of Neurology from the University of Lodz, Poland for providing tissue specimens.

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