Brain miliary enhancement

CNS lymphoma might be either secondary to systemic lymphoma (the most common disease causing a military enhancement pattern) or primary CNS lymphoma (PCNSL), in which the tumour is restricted to the brain, leptomeninges, spinal cord and/or eyes, without involvement of tissues outside the CNS [4].

Aggressive non-Hodgkin lymphoma is the most frequent cause of secondary CNS lymphoma. Approximately two thirds of the patients with cerebral involvement in aggressive non-Hodgkin lymphoma present with leptomeningeal spread, while one third show parenchymal disease [4]. Leptomeningeal spread often affects the cranial nerves, spinal cord and spinal roots, and it may present as cranial or spinal neuropathies [5]. Headache is reported in almost half of the patients with leptomeningeal metastases, and it may be caused by increased intracranial pressure from metastatic obstruction of CSF flow/absorption [4]. The common neuroimaging features of meningeal metastases include arachnoidal, subependymal, dural or cranial nerve enhancement; superficial cerebral lesions; and communicating hydrocephalus [5]. Parenchymal metastases from non-Hodgkin lymphoma often appear as single or multiple enhancing lesions and can be accompanied by leptomeningeal metastases or, sporadically, with a pattern of miliary enhancement characterized by multiple CNS punctate and curvilinear lesions [4, 6, 7]. Cytology of the CSF usually shows malignant cells [8]. CNS lymphoma is very responsive to treatment with corticosteroids, shrinking dramatically within a few days of steroid administration due to their combined cytotoxic (reducing the neoplastic mass) and anti-oedema effects [8].

PCNSL typically affects patients older than 50 years, and male-to-female ratio is approximately 2:1 [2]. CSF examination occasionally shows malignant cells and increased protein concentration [9], and the treatment of choice relies on corticosteroids and chemotherapy [8, 9]. PCNLS can affect both immunocompetent and immunodeficient patients. In immunocompetent patients, PCNSL typically presents as a solitary homogeneously enhancing parenchymal mass, even though multiple lesions are reported in the 20–40% of the cases and ring-like enhancement in 0–13% [4]. Linear enhancement along perivascular spaces is highly suggestive of PCNSL [10]. Most lesions are located in central hemispheric or periventricular cerebral white matter, but superficial location adjacent to the meninges is also common [4]. The brainstem, cerebellum and spinal cord can also be affected [4]. The presence of haemorrhages or calcifications within the tumour is quite a rare finding [11]. On the other hand, immunodeficient patients with PCNSL are often diagnosed with multifocal lesions (30–80% of patients with AIDS-related PCNSL) [4]. Because many lesions exhibit necrotic regions, contrast enhancement is commonly irregular or peripheral, with a ring-like appearance. The basal ganglia and corpus callosum are frequently involved and spontaneous haemorrhage in PCNSL lesions may be more frequent than in immunocompetent patients [4].

Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive lymphoproliferative disease [12]. The granulomatous reaction targets mostly the lungs, but it may also involve the kidneys, skin and the CNS [13]. In the rare case of isolated CNS-lymphomatoid granulomatosis, prognosis is better than systemic lymphomatoid granulomatosis with CNS involvement [12]. On MR imaging, enhancing mass-type lesions may be seen, but multiple miliary and linear enhancements seem to be the more specific findings, as the disease affects preferentially perivascular tissues and the walls of vessels [12]. In addition, leptomeningeal enhancement and dural and cranial nerve enhancement have been reported [12].

Sarcoidosis usually presents as a systemic granulomatous disease with lymphadenopathy, pulmonary infiltration, cardiac and musculoskeletal manifestations and lesions in the skin, liver and eye [14]. Young adults aged 25–45 are most commonly affected, and the incidence depends on age and geography, being higher in non-Caucasian ethnicities and women [14]. About 5% of patients with systemic sarcoidosis may show CNS involvement, whereas isolated neurosarcoidosis, i.e. strictly confined to the CNS, is rare [15]. Diagnostic work-up for systemic sarcoidosis should include serum angiotensin-converting enzyme and human soluble interleukin-2 receptor/CD25, ophthalmological examination, conjunctival biopsy, chest X-ray or CT scan, hand X-ray, bronchial lavage, bronchoscopy and biopsy and lymph node biopsy [14]. Therapy relies on corticosteroids [14].

Central nervous system involvement is very variable, with lesions potentially involving the pachymeninges and leptomeninges (seen in up to 40% of cases), pituitary gland and hypothalamus, cranial nerves and brain parenchyma [15, 16]. Therefore, headache and cranial nerve palsy are common clinical presentations (30–50% of cases), and the facial nerve is very frequently involved, followed by the optic and the vestibulocochlear nerves [14]. Spinal sarcoidosis is relatively common and can manifest with intramedullary, intradural–extramedullary or extradural lesions; cauda equina syndrome; and arachnoiditis [15]. CSF analysis is non-specific, showing increased protein concentration, pleiocytosis and oligoclonal bands. The spectrum of brain MRI abnormalities consists of pachymeningeal involvement, leptomeningeal enhancement (with pituitary, hypothalamic and cranial nerve involvement) and parenchymal lesions (Fig. 4a) [15, 16]. Parenchymal involvement is the most common finding and can manifest in different ways, including extension of leptomeningeal inflammation along PVS, periventricular white matter lesions similar to multiple sclerosis and enhancing masses and nodules [16, 17]. A distribution pattern consistent with PVS involvement has been reported [16, 17], and also in our experience, involvement of the PVS is common (Fig. 2a).

Erdheim–Chester disease (ECD) is a rare systemic non-Langerhans form of histiocytosis affecting especially the long bones, the lungs and the retroperitoneum [18]. Characteristic X-ray images of long tubular bones show patchy sclerotic lesions with symmetrical involvement of both metaphysis and diaphysis and epiphyseal sparing (Fig. 5e) [18]. Although the age range of patients is wide, ECD typically affects middle-aged or elderly (mean age of 53) males, with a male-to-female ratio of 3:1 [19]. Clinical manifestations are non-specific bone pain and neuroendocrine disturbances, especially diabetes insipidus, which is caused by hypothalamic–sellar masses [19]. Neurological involvement is encountered in less than 50% of cases with the most common localisation including hypothalamic–pituitary axis, brain parenchyma, orbits, meninges and paranasal sinuses [19]. Meningeal involvement occurs in 23% of patients, presenting as single or multiple dural masses that are ‘meningioma-like’, or diffuse pachymeningeal thickening [19]. CSF analysis is non-specific, showing increased protein concentration, low glucose levels and normal cell count. Lumbar puncture is not revealing since ECD histiocytes are rarely present in the CSF and, so far, there are no effective treatment options [20]. Neuroimaging findings include mostly extra-axial, intracranial lesions in the retro-orbital space, pituitary stalk, cerebellopontine angle, choroidal plexus, dura and falx. Spinal cord involvement has also been described [18]. Perivascular distribution has been reported, including extension along the PVS at the level of the basal ganglia, the pons and dentate nuclei, to be possible (Fig. 2b) [2].

Vitamin B₁₂ deficiency can affect both sexes, all economic classes and all ages. High levels of suspicion of inherited vitamin B₁₂ metabolism defects should be maintained in children, while elderly individuals might demonstrate the deficiency due to pernicious anaemia or alcohol abuse. In the adults, the condition frequently appears as a result of malabsorption of vitamin B₁₂ due to small intestine diseases or therapies which interfere with B₁₂ absorption [21, 22]. Also, recreational use of nitrous oxide is spreading rapidly as a cause in young adults [23]. In combination with folic acid, B₁₂ is considered crucial in proliferation, maturation and regeneration of neural cells [22]. Serum active B₁₂ is the earliest detectable marker that will reveal a deficiency, and methyl malonic acid will increase when vitamin B₁₂ storages are depleted [22]. In adulthood, neurological manifestations due to vitamin B₁₂ deficiency occur in both sexes across age groups, but the median age range in large series is 70 years to 80 years [22]. The most common clinical finding is symmetric and progressive peripheral neuropathy [21, 22, 24]. CSF analysis could show low levels of transcobalamin II and vitamin B₁₂. The administration of vitamin B₁₂ supplement may lead to the resolution of the spinal and cranial abnormalities [22]. Cognitive impairment has also been reported as a result of vitamin B₁₂ deficiency neurological syndrome, even though replacement therapy is ineffective at this stage [21]. Spinal cord MRI classically shows dorsal column involvement (Fig. 6a, b) and, at a later stage, cord atrophy [24]. Brain involvement might demonstrate extensive areas of a high-intensity signal in the periventricular white matter, and in children with inherited cobalamin-related diseases, brain damage is characterized by white matter loss with delayed myelination [25]. We did not find reports describing miliary PVS enhancement; however, in our experience, this may be seen (Fig. 1).

The two CNS vasculitis described with brain miliary enhancement at MRI are primary angiitis of the central nervous system (PACNS) and secondary CNS vasculitis due to chronic graft versus host disease [26, 27].

PACNS, also known as granulomatous angiitis or isolated cerebral vasculitis, leads to a wide spectrum of clinical manifestations including diffuse or focal throbbing headaches, focal or generalized seizures, encephalopathy, brainstem events, stroke-like episodes, aphasia, myelopathy and diffuse neurological dysfunction [26]. Although vessels of any size may be involved, small- and medium-sized ones are most commonly targeted [28]. Males are affected twice as often as females and the onset usually occurs after 40 years of age [26]. Leptomeningeal biopsy can provide a definitive diagnosis, but this procedure is not routinely performed also in light of the fact that a negative biopsy does not rule out the condition [26]. CSF examinations reveal pleiocytosis and increased protein levels [26]. Both clinical and radiological improvements are achieved after high-dose corticosteroids and cyclophosphamide administration [26]. An unremarkable MRI is a very strong argument against the diagnosis of PACNS, and it might serve to exclude it from the differential diagnosis. MRI findings in PACNS include multiple bilateral supratentorial lesions affecting both the grey matter and the white matter, occasionally in combination with diffusion restriction [28]. Leptomeningeal enhancement occurs in 10–15% of the cases [29]. Frequently, segmental vascular lesions may complicate into stenoses, occlusions and infarctions [28], which are often accompanied by white matter hyperintensities [29]. Angiography is considered the gold standard for imaging evaluation, but its sensitivity in detecting PACNS remains limited to the 50–90% range [29]. Angiography may reveal multiple arterial abnormalities such as avascular areas, including uncommon cases of cerebral infarctions along small arterial territories, segmental stenoses, intracerebral aneurysms and narrowing of intracranial vessels eventually alternated by focal dilatations forming a so-called ‘string of beads’ appearance [29, 30]. Aneurysmal rupture leads to either subarachnoid or parenchymal haemorrhage [28]. Salvarani et al. [31] documented spinal cord involvement in about 5% of cases in a study involving 101 patients (Fig. 6d). PVS distribution of miliary-enhancing nodules has been described in PACNS (Fig. 2d) [28].

Secondary vasculitis due to chronic graft versus host disease after haematopoietic stem cell transplantation may also show military enhancement on brain MRI. Terada et al. [27] and Sostak et al. [32] described a brain miliary enhancement along the path of the PVS likely due to the small vessel disruption, either by the direct injury of the endothelial cells or by angiocentric infiltrates composed of various combinations of T lymphocytes, B lymphocytes and histiocytes.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPPERS) is a pontine-predominant encephalomyelitis, and it was first described in a small group of 8 patients in 2010 as a clinically and radiologically distinct entity [33]. A review by Dudesek et al. [34] described 56 cases worldwide in 2014, with a male predilection and a median age at onset of 52 years (range 16–86 years). Clinical manifestations include ataxia, diplopia, dizziness, nausea, dysgeusia and pseudobulbar affect among others, but there were no reports on systemic symptoms such as weight loss, fever or lymphadenopathy [33, 34]. The pathogenesis remains still unknown, but it could be autoimmune or inflammatory-mediated, and CSF analysis may reveal elevated oligoclonal bands [34].

Recent diagnostic criteria published by Tobin et al. [35] in 2017 include clinical, radiological and pathological features to discriminate CLIPPERS from non-CLIPPERS aetiology, including the presence of (a) homogenous, gadolinium-enhancing nodules without ring enhancement or mass effect predominating in the pons and cerebellum, measuring < 3 mm in diameter and a pattern consistent with PVS involvement (Fig. 2c); (b) marked improvement in abnormal gadolinium enhancement after corticosteroid treatment (Fig. 7); (c) homogenous T2 signal abnormality not significantly exceeding the size of the area of gadolinium enhancement; and (d) spinal cord lesions with similar T2 and gadolinium-enhancing lesions as above [35]. Recently, these diagnostic criteria have been evaluated by Taieb et al. [36] and suggested to consider nodular enhancement as an unusual finding more than a red flag for excluding the diagnosis of CLIPPERS.

In addition to MRI of the brain and the spinal cord, various additional imaging investigations have been performed in CLIPPERS patients and usually revealed no decisive findings. PET-CT of the brain showed no change or minor hypermetabolism of contrast-enhancing areas, considerably less than the findings usually reported in lymphoma [34].

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory disorders of the CNS characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord, in which the high specificity of aquaporin-4 (AQP4)–immunoglobulin G (IgG) has allowed to recognize other sites of CNS involvement not restricted to the optic nerves and spinal cord as well as diencephalon, brainstem and the brain [37]. Typical MRI findings in NMOSD have been reported as confluent, asymmetric T2 hyperintensities usually distributed in periependymal areas, following the ependymal lining of the lateral, third and fourth ventricles, particularly close to the cerebral aqueduct. The ependymal surfaces of the corpus callosum, diencephalic region and brainstem have also been assumed as typical locations for NMOSD brain lesions [37]. NMOSD scans may occasionally show a ‘cloud-like’ pattern of gadolinium enhancement, with a patchy and inhomogeneous appearance and poorly defined margins; also, periependymal and leptomeningeal enhancements are common [38]. Leptomeningeal enhancement may be thick or linear and is possibly due to AQP4 channel impairment on the pial and subpial surfaces [38]. Pekcevik and Izbudak [39] described a perivascular enhancement pattern during an acute optic neuritis attack in a patient with NMOSD diagnosis, suggesting that PVS enhancement may be seen in NMOSD patients in addition to periependymal and leptomeningeal enhancements. Therapeutic options for acute presentation as well as long-term immunosuppressive treatment include azathioprine, rituximab, immunoglobulins and corticosteroid [37].

Glial fibrillary acidic protein (GFAP) meningoencephalomyelitis is a relapsing, autoimmune, corticosteroid-responsive disorder, which sometimes develops as a paraneoplastic autoimmune meningoencephalomyelitis [40]. The detection of GFAP-IgG in serum is a pathognomonic finding [40], while the presence of neuronal, glial or skeletal muscle–specific IgG in serum or CSF aids diagnosis and guides therapy [40, 41]. Fang et al. [41] described a case series of 103 patients with a wide age range (21–73 years, median age of 42 years) and no sex predominance. Clinical manifestations included headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor and cerebellar ataxia. Imaging revealed linear perivascular enhancement that resembles the filamentous pial, subventricular and perivascular immunostaining pattern recognisable on murine models [40]. Other enhancement patterns observed less frequently included leptomeningeal and ependymal [40].

The most frequent spinal MRI finding of GFAP autoimmunity is a longitudinally extensive T2-hyperintense lesion, with thin and linear enhancement along the course of the central canal [40].

Behçet’s disease is a multisystem inflammatory disease of unknown origin, presumably autoimmune in nature and mostly affecting patients from Japan or Mediterranean countries [42]. Onset before the age of 10 and after the age of 50 is rare. The disease shows a male predominance in the Mediterranean region while women are more commonly affected in the Far East [42, 43]. CNS involvement occurs in 10–30% of Behçet’s patients, generally 4–6 years after the disease onset [42, 44]. The clinical presentation of systemic Behçet’s disease shows recurrent oral aphthae (at least 3 times per year in 97% of cases), accompanied by any two of the following: genital ulcers which heal with scarring, erythema nodosum (in 60% of cases), folliculitis, uveitis, skin reactions and hyper-reactivity [42, 45]. Behçet’s disease is responsive to corticosteroid administration [42].

Neuro-Behçet’s disease most commonly presents with bilateral pyramidal signs, hemiparesis and behavioural changes [42]. CSF findings are non-specific, revealing increased protein concentration and pleiocytosis [45]. Typically, the lesions are clustered in the brainstem with a preference for the mesodiencephalic or pontobulbar regions (with typical sparing of the red nuclei), basal ganglia and cerebellar peduncles, and spinal cord involvement is very rare (Fig. 7) [46]. In later stages, brainstem atrophy is a characteristic feature [42]. Furthermore, meningeal involvement, venous thrombosis and delayed intracerebral haemorrhages have been reported [42, 44]. Increased intravascular pressure caused by thrombotic occlusion of the proximal venules and sustained extravasation of erythrocytes via the disrupted walls of small vessels have been proposed as possible causes of the delayed hematoma development typical of Behçet’s disease [44]. This is a different mechanism from arterial haemorrhages, which cause sudden and rapid neurologic deteriorations, or from haemorrhagic transformation of arterial infarctions, also showing an acute onset [44]. Histopathologically, perivascular inflammation has been described in Behçet’s disease [44, 45, 47], but a PVS pattern of enhancement has not yet been reported as an MRI feature. One explanation could be that the absence of endothelial degeneration supports a perivascular inflammatory process as opposed to a vasculitis, and this is not sufficient to cause an evident perivascular enhancement [47]. Given the vascular aetiology of the disease, we decided to consider neuro-Behçet’s disease as part of the group with PVS distribution of enhancement. Moreover, in our case series, we found a CLIPPERS-like infratentorial pattern of miliary enhancement, which can support the thesis of its vascular involvement also in brain imaging.

Different infectious diseases might present with a miliary pattern of cerebral enhancement, and immunocompromised patients are subjects at high risk [2]. The most frequent infectious disorders which present with miliary enhancement are Lyme disease, Candida albicans, Cryptococcus, progressive multifocal leukoencephalopathy (PML) caused by the opportunistic infection by John Cunningham (JC) virus in immunocompromised patients or patients with MS treated with natalizumab therapy, neurotuberculosis and histoplasmosis, the last two without a PVS pattern of enhancement. CNS infections do not respond to corticosteroid therapy, but they need specific antibiotic or antifungal therapies. As neurotuberculosis and histoplasmosis show an atypical enhancement pattern with respect to all other infectious diseases, they will be described in the following paragraphs.

Tuberculosis can occur at any age, most often in the first three decades of life, with no sex predominance [68]. Frequently reported manifestations of tuberculosis involving the CNS are alterations of consciousness, focal neurological signs, behavioural changes, intracranial hypertension and seizures [68, 69]. CSF examination could show a positive polymerase chain reaction (PCR) and positive culture for TB [68]. Treatment of choice consists of a multidrug approach with isoniazid, rifampicin and pyrazinamide; corticosteroids will not produce an adequate response and are contraindicated [68]. Intracranial tuberculosis can be broadly divided into meningeal and parenchymal patterns of involvement, and any combination of the patterns can occur [70]. Meningeal tuberculosis can be either leptomeningeal or pachymeningeal. Tubercular leptomeningitis is the most common manifestation of CNS tuberculosis, and it is frequently associated with complications like hydrocephalus, ventriculitis and choroid plexitis (Fig. 4b) [70]. Parenchymal tuberculosis, instead, consists of tuberculomas, cerebritis, abscesses, rhombencephalitis and encephalopathy [70]. Parenchymal tuberculomas are the most common form of intracranial parenchymal tuberculosis due to conglomeration of tubercular microgranulomas, which tend to occur at the grey–white matter junction due to arrest of the haematogenous spread caused by a reduction in the calibre of the vessels in that region [70]. Miliary tuberculomas, mostly seen in immunocompromised patients, are usually diffusely scattered in the brain parenchyma, are predominantly located at the grey–white matter junction and occur when the infection reaches the brain through haematogenous spread, usually from a pulmonary focus (Fig. 3a) [69, 70]. No PVS involvement has been reported. Extra-axial spinal tuberculosis could manifest as tuberculous spondylodiscitis (Fig. 5a) [69].

The term ‘miliary tuberculosis’ refers to an uncommon pulmonary manifestation of tuberculosis and represents hematogenous dissemination of uncontrolled tuberculous infection with a poor prognosis (Fig. 5b) [69].

Histoplasmosis is mainly a pulmonary disease caused by the inhalation of the spores of the fungus Histoplasma capsulatum [71]. Patients on immunosuppressive agents, transplant recipients and those affected by either AIDS or haematological malignancies are at risk because of their ineffective immune defences [71]. This fungus is endemic in Northern and Central America, Asia and Africa, which have the highest prevalence, but it also exists in other parts of the world [71]. Usually, this disease is asymptomatic, but older and immunosuppressed patients might present pulmonary findings such as cavitary lesions, granulomatous necrotic mediastinitis and mediastinal fibrosis [72]. In the case of disseminated disease, other organs such as the liver, spleen, bone marrow, lymphoreticular system and, less commonly, the skin are affected [73]. Approximately 5–10% of patients with disseminated histoplasmosis have clinically apparent CNS involvement [71]. Clinical presentation generally reflects the effects of single or multiple space-occupying brain lesions, with headache, focal deficits, altered mental state, stroke-like syndromes and encephalitis [71]. Most lesions clear with antifungal therapy in which posaconazole is most effective [73]. CSF analysis might reveal elevated antibodies against Histoplasma capsulatum, and non-specific findings like increased protein concentration, depressed glucose levels and pleiocytosis [71]. Chronic, mainly basilar, meningitis and multiple small ring- or nodular-enhancing lesions throughout the brain and spine are the common findings in CNS involvement (Figs. 3d and 6c) [72]. In the appropriate endemic context, cerebral histoplasmosis should be a diagnostic consideration when imaging studies show multiple brain lesions [73]. There have been no reports of distribution along the PVS.

Susac’s syndrome is a rare and presumably autoimmune-mediated disease affecting the small arteries of the brain, inner ear and retina. The clinical triad comprising brain involvement with encephalopathy, hearing loss and branch retinal artery occlusions (Fig. 5d) is considered pathognomonic but is complete only in a minority of patients at disease onset [74]. Other manifestations include headache, confusion, memory loss, dysarthria, behavioural changes, tinnitus and vertigo [75]. Susac’s syndrome mainly affects women aged 20–40 (male-to-female ratio of 1:3) [75]. CSF findings are non-specific, showing pleiocytosis and increased protein concentration [74, 75]. Therapy of choice is corticosteroids; cyclophosphamide can be added as a second-line treatment when corticosteroids fail to produce an adequate response. A review of 27 patients by Susac et al. [76] describes typical involvement of the corpus callosum, the periventricular and subcortical white matter and white matter in the centrum semiovale (100% of cases) (Fig. 3b). Grey matter involvement is less frequent (70% of cases) as well as the presence of enhancing grey and white matter lesions (also 70% of cases). Leptomeningeal enhancement is reported in 33% of cases [76]. The widespread white and grey matter involvement appears not to show a distribution pattern along the PVS. Due to the rarity of Susac’s syndrome, MRI spinal cord involvement has not been well characterized likely due to a lack of routine spinal MRI being performed, but it has been rarely described [77].

Miliary dissemination is a rare manifestation of brain metastases, and it presents as diffuse miliary spread of punctate tumour nodules often with a PVS distribution without invasion of the brain parenchyma, but a non-PVS distribution is also possible (Fig. 3c) [78]. A limited number of autopsy studies confirmed miliary-enhancing lesions in metastatic disease. This rare presentation has been reported mostly in metastatic lung adenocarcinoma [79], but it has been also described in metastatic melanoma [80] and in other types of adenocarcinoma, including breast carcinoma, pancreatic, gastric and salivary gland tumours [78]. Usually, the grey–white matter junction is the preferred site of metastatic carcinomatous cells and metastases may vary in size [79]. Leptomeningeal carcinomatosis resulting from diffuse infiltration in the subarachnoid space also occurs in about 3% of patients with malignancy, usually from the lung, breast or gastric carcinomas [79]. CSF analysis in metastatic disease shows low levels of glucose, increased protein concentration and pleiocytosis and, occasionally, the presence of tumour cells [79]. Treatment of choice should be based on the clinical picture, but it often includes chemotherapy possibly in combination with whole-brain radiotherapy. The administration of corticosteroids might temporarily reduce the perilesional vasogenic oedema and hence relieve symptoms [79].