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 .
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 . Leptomeningeal spread often affects the cranial nerves, spinal cord and spinal roots, and it may present as cranial or spinal neuropathies . 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 . The common neuroimaging features of meningeal metastases include arachnoidal, subependymal, dural or cranial nerve enhancement; superficial cerebral lesions; and communicating hydrocephalus . 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 . 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 .
PCNSL typically affects patients older than 50 years, and male-to-female ratio is approximately 2:1 . CSF examination occasionally shows malignant cells and increased protein concentration , 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% . Linear enhancement along perivascular spaces is highly suggestive of PCNSL . Most lesions are located in central hemispheric or periventricular cerebral white matter, but superficial location adjacent to the meninges is also common . The brainstem, cerebellum and spinal cord can also be affected . The presence of haemorrhages or calcifications within the tumour is quite a rare finding . On the other hand, immunodeficient patients with PCNSL are often diagnosed with multifocal lesions (30–80% of patients with AIDS-related PCNSL) . 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 .
Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive lymphoproliferative disease . The granulomatous reaction targets mostly the lungs, but it may also involve the kidneys, skin and the CNS . In the rare case of isolated CNS-lymphomatoid granulomatosis, prognosis is better than systemic lymphomatoid granulomatosis with CNS involvement . 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 . In addition, leptomeningeal enhancement and dural and cranial nerve enhancement have been reported .
Sarcoidosis usually presents as a systemic granulomatous disease with lymphadenopathy, pulmonary infiltration, cardiac and musculoskeletal manifestations and lesions in the skin, liver and eye . 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 . About 5% of patients with systemic sarcoidosis may show CNS involvement, whereas isolated neurosarcoidosis, i.e. strictly confined to the CNS, is rare . 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 . Therapy relies on corticosteroids .
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 . Spinal sarcoidosis is relatively common and can manifest with intramedullary, intradural–extramedullary or extradural lesions; cauda equina syndrome; and arachnoiditis . 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 . 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) . 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 . Clinical manifestations are non-specific bone pain and neuroendocrine disturbances, especially diabetes insipidus, which is caused by hypothalamic–sellar masses . 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 . Meningeal involvement occurs in 23% of patients, presenting as single or multiple dural masses that are ‘meningioma-like’, or diffuse pachymeningeal thickening . 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 . 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 . 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) .
Vitamin B12 deficiency
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 . In combination with folic acid, B12 is considered crucial in proliferation, maturation and regeneration of neural cells . 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 . 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 . 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 . Cognitive impairment has also been reported as a result of vitamin B12 deficiency neurological syndrome, even though replacement therapy is ineffective at this stage . Spinal cord MRI classically shows dorsal column involvement (Fig. 6a, b) and, at a later stage, cord atrophy . 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 . We did not find reports describing miliary PVS enhancement; however, in our experience, this may be seen (Fig. 1).
Primary and secondary CNS vasculitis
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 . Although vessels of any size may be involved, small- and medium-sized ones are most commonly targeted . Males are affected twice as often as females and the onset usually occurs after 40 years of age . 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 . CSF examinations reveal pleiocytosis and increased protein levels . Both clinical and radiological improvements are achieved after high-dose corticosteroids and cyclophosphamide administration . 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 . Leptomeningeal enhancement occurs in 10–15% of the cases . Frequently, segmental vascular lesions may complicate into stenoses, occlusions and infarctions , which are often accompanied by white matter hyperintensities . Angiography is considered the gold standard for imaging evaluation, but its sensitivity in detecting PACNS remains limited to the 50–90% range . 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 . Salvarani et al.  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) .
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.  and Sostak et al.  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
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 . A review by Dudesek et al.  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 .
Recent diagnostic criteria published by Tobin et al.  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 . Recently, these diagnostic criteria have been evaluated by Taieb et al.  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 .
Neuromyelitis optica spectrum disorders
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 . 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 . 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 . Leptomeningeal enhancement may be thick or linear and is possibly due to AQP4 channel impairment on the pial and subpial surfaces . Pekcevik and Izbudak  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 .
Glial fibrillary acidic protein meningoencephalomyelitis
Glial fibrillary acidic protein (GFAP) meningoencephalomyelitis is a relapsing, autoimmune, corticosteroid-responsive disorder, which sometimes develops as a paraneoplastic autoimmune meningoencephalomyelitis . The detection of GFAP-IgG in serum is a pathognomonic finding , 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.  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 . Other enhancement patterns observed less frequently included leptomeningeal and ependymal .
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 .
Behçet’s disease is a multisystem inflammatory disease of unknown origin, presumably autoimmune in nature and mostly affecting patients from Japan or Mediterranean countries . 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 .
Neuro-Behçet’s disease most commonly presents with bilateral pyramidal signs, hemiparesis and behavioural changes . CSF findings are non-specific, revealing increased protein concentration and pleiocytosis . 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) . In later stages, brainstem atrophy is a characteristic feature . 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 . 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 . 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 . 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 . 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.
Systemic borreliosis is considered the most common vector-borne illness caused by spirochetes of the Borrelia burgdorferi species [48, 49]. Multiple organ systems may be involved, including the heart, joints, skin, eyes and the CNS, in which case it is referred to as neuro-Lyme disease . Three stages of Lyme disease are identified. First is a prodromal stage with flu-like symptoms and an expanding annular rash, also referred to as erythema migrans (Fig. 5c), 2–30 days after the tick bite. Secondly, both cardiac and neurological symptoms manifest 1–4 months after the bite, followed by arthritis and chronic neurological symptoms which are present after one or more years . The neurological manifestations include peripheral neuropathies, radiculopathies, myelopathies, encephalitis, meningitis, cerebellar signs, cognitive and movement disorders and cranial nerve palsies . Facial nerve palsy is common in neuro-Lyme disease, with bilateral involvement in 50% of cases, and it is considered a rather disease-specific finding (Fig. 4c) . CSF analysis shows reduced glucose levels, increased protein concentration and pleiocytosis, and it is therefore non-specific . Treatment of choice is based on antibiotics . MRI rarely reveals brain lesions, but both meningeal and nerve root involvements are relatively common features [50, 51]. Focal hyperintense T2 multiple sclerosis–like lesions of cerebral white matter have also been reported . Spinal cord involvement by Borrelia burgdorferi, on the other hand, is very rare . Cerebral vasculitis in neuro-Lyme disease can affect small-sized as well as medium- and large-sized intracranial arteries, a recent study report on predominant anterior circulation vasculitis in addition to reported PVS involvement .
Candida albicans is a severe fungal infection affecting mostly immunocompromised hosts suffering from HIV and leukaemia, patients with indwelling catheters and premature neonates with significant low birth weight . Reported mortality rates can be as high as 35% of infected cases. Candida albicans species demonstrate tropism to a variety of tissues of different organs, including the brain. During the hematologic dissemination phase, known as candidemia, the fungus travels along the bloodstream, with the potential of infecting all the perfused organs [53, 54]. Clinical presentation consists of mucocutaneous candidiasis and systemic candidiasis leading to isolated organ failure or multiorgan failure such as meningitis, endocarditis, peritonitis, osteomyelitis and septic arthritis . Diagnosis can be based on CSF analysis, showing pleiocytosis, decreased glucose and increased protein concentrations and CSF cultures, with positivity estimated around 80% . Management requires antifungal therapy, preferably based on a combination of amphotericin B and flucytosine, and supportive care . Meningitis occurs frequently, and it is classically characterized by headache, neck stiffness and fever. The presence of multiple intracranial (micro) abscesses has also been reported . Mouse studies have revealed adhering and binding of Candida albicans to the endothelium of cerebral blood vessels followed by the invasion of the brain parenchyma [55, 56], which might explain intracranial abscesses. Autopsy studies demonstrated that the supratentorial grey–white joint at the level of the basal ganglia is the most affected area in CNS candidiasis . To a lesser extent, Candida can cause the development of mycotic aneurysms resulting in intracerebral haemorrhage or subarachnoid haemorrhage, thrombosis in small perforating arterioles resulting in ischaemic stroke, cerebral macro-abscesses and cerebral vasculitis .
CNS cryptococcosis results from the infection of the CNS by the yeast-like fungus Cryptococcus neoformans, and it is the most common fungal infection and the second most common opportunistic infection of the CNS . The strongest risk factor for infection is T cell dysfunction, especially due to HIV infection. The fungal spores in the dehydrated state are small enough to be inhaled and cause an asymptomatic lung infection followed by meningitis . The most common clinical findings in CNS cryptococcal infection are headache, nausea and fever. Less common manifestations are meningism, altered mental state, seizures, visual symptoms and focal neurological deficits . The brain regions most commonly affected are the basal ganglia and meninges. In the basal ganglia, a localized cluster of organisms may develop gelatinous pseudocysts . Cryptococcomas (accumulations of fungi, inflammatory cells and gelatinous mucoid material) appear during the infection and can extend to the parenchyma as focal masses with a tumour-like appearance . Duarte et al.  aimed to describe the imaging patterns associated with CSN infection with Cryptococcus species in relation to the patient’s immune status (immunocompetent and immunocompromised), describing the dilatation of the perivascular spaces as a common finding in both groups of patients but finding also a perivascular miliary nodule enhancement pattern in one HIV patient with AIDS. Spinal cord infection caused by Cryptococcus is rare but might be seen in immunocompromised hosts .
Progressive multifocal leukoencephalopathy with immune reconstitution inflammatory syndrome (PML-IRIS)
PML is a progressive demyelinating disorder that results from a viral infection of the myelin-producing oligodendrocytes by the JC papovavirus . PML develops from a latent JC virus infection during childhood or early adolescence, which can be reactivated in the setting of immunodeficiency, currently most frequently in multiple sclerosis patients treated with natalizumab . The risk of natalizumab-associated PML increases proportionally to the duration of treatment, with the greatest risk after 2 years of therapy . PML typically results in progressive neurological decline, cognitive impairment, altered mental status and personality changes. Motor and sensory changes also occur, and patients may develop seizures . Spinal cord involvement is extremely rare and only occasionally reported .
Current prophylaxis and treatment of PML focus on restoration of immune responses to JC virus infection and interruption of treatment with natalizumab, which might cause an over-reaction of the immune system. The associated immune reconstitution inflammatory syndrome (PML-IRIS) is clinically characterized by new clinical symptoms and/or worsening of existing clinical symptoms mirrored by progressive imaging findings of active inflammation, like contrast enhancement and rapid progression of existing PML lesions showing mass effect with swelling and oedema . PML-IRIS is treated with high-dose glucocorticoids . Since even in early stages PML and PML-IRIS can occur simultaneously, it is crucial to have an early correct imaging-based diagnosis because glucocorticoid therapy for a false-positive PML-IRIS at the stage of productive JC virus infection might lead to PML re-activation and progression . Wattjes et al.  described the early PML-IRIS imaging findings in a clinical cohort of 24 subjects with natalizumab-associated PML-IRIS, discovering that, in approximately one third of subjects, one of the earliest signs of PML-IRIS was the presence of small punctuate foci of contrast enhancement with a PVS distribution, peripherally with respect to the main PML lesion. These features were described also by Langer-Gould et al. , and this imaging phenomenon is supported by histopathology data demonstrating an inflammatory reaction of B cells as well as CD8+ T lymphocytes outside the main PML lesions, particularly in the PVS of patients with PML-IRIS .