Tumor-related enhancement

Malignant tumors can cause CNE mainly through two routes of tumor spread: perineural tumor spread (PNTS) and leptomeningeal carcinomatosis (LC)/neurolymphomatosis. The MRI detection of these pathological conditions is crucial because they correlate with decreased survival, and PNTS also increases locoregional recurrence.

Malignant cells can dissociate from the primary tumor and establish metastatic deposits at nearby or distant sites. Metastatic deposits in and along nerves result in pathological enhancement and thickening, commonly with a micronodular appearance. Due to the pathogenic mechanisms, cranial nerve involvement is generally unilateral in the case of perineural spread and bilateral in leptomeningeal carcinomatosis and neurolymphomatosis [24, 34].

A malignancy spreads centripetally from the initial tumor site into the central nervous system using the support of a nearby nerve in a process known as perineural tumor spread (PNTS). The term perineural tumor invasion (PNTI) is often mistakenly used as a synonym for PNTS. It is important to clarify that while PNTI refers to a histologic finding of tumor cell infiltration, PNTS refers to the macroscopic involvement, radiologically apparent with a sensitivity of 95% on MRI [25].

In the literature, it is reported commonly in head and neck cancer, reaching up to 50–70% in patients affected by mucosal squamous cell cancer and in at least half of patients affected by adenoid cystic carcinoma [21, 25].

The exact mechanism by which PNTS occurs is unclear, but modern studies have demonstrated that it is the result of a dynamic molecular process involving active crosstalk between the tumor and nerve cells [25, 26]. It has been proven that proteins involved in neural homeostasis, axonogenesis, and dendritic growth play a key role in cancer cell proliferation, perineural invasion, and migration. These proteins are numerous including brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, neurotrophin-4, glial cell line-derived neurotrophic factor, the neural cell adhesion molecule, substance P, laminin-5, semaphorins, and their receptors [26, 27].

Since it is typically a unilateral process, the most characteristic MRI finding of PNTS is an asymmetrical enlargement and enhancement (monolateral thickened pattern) of the involved cranial nerve compared to the healthy contralateral nerve. Additional findings include obliteration of perineural fat planes, denervation changes, and homolateral widening of foramina [25] (Fig. 6).

Fig. 6

Patient with a history of oral cavity cancer treated by left hemiglossectomy with temporal flap reconstruction visible in a. (arrow) axial T1-weighted image. The axial T1-weighted image in b shows obliteration of the left pterygopalatine fossa by a pathological enhancing tissue well visible in c coronal fat-saturated 3D T1 post-contrastographic weighted images (circle). In d axial fat-saturated 3D T1 post-contrastographic weighted images it is visible a thickened enhancement extending to the V2 segment of the left trigeminal nerve (arrow) and in e axial and f coronal fat-saturated 3D T1 post-contrastographic weighted images a thickened enhancement of the ipsilateral V3 segment (arrow). These findings are consistent with perineural spread

Although skip lesions are uncommon, they are theoretically possible in the case of PNTS, where the tumor tissue is often continuous down the nerve [25, 27].

Due to its size, cranial nerve V is the most affected nerve. Yet, cranial nerves III, IV, and VI can all be affected because of their intracavernous tracts' location within CN V [25].

Another possible cause of CNE in patients with head and neck tumors, in differential diagnosis with PNTS, is related to complications of radiotherapy causing the so-called radiation-induced neuritis. Radiotherapy may induce loss of BNB integrity due to demyelination, ischemia, coagulation necrosis, or peripheral fibrosis. In radiation-induced neuritis, the affected nerves usually appear thickened with T2 hyperintense signal and enhancement. Although all cranial nerves could be potentially involved, depending on the radiation exposure, literature data reported the XII cranial nerve as the most affected nerve following irradiation for nasopharyngeal carcinoma. Two conditions could help in differentiating radiation-induced neuritis from PNTS, the type of CNE usually more nodular in PNTS, and the timing of onset usually months to years after radiation therapy exposure in radiation-induced neuritis [1].

The other route of tumor spread already mentioned is leptomeningeal carcinomatosis. This condition refers to a metastatic involvement of the cerebrospinal fluid and leptomeninges by a central nervous system tumor, any solid systemic tumor, or hematologic malignancy. In the literature, it is reported to occur in 4–15% of patients with malignancy, and, in decreasing order, breast cancer, lung cancer, and melanoma are the most common systemic cancers involved [14] (Fig. 7).

Fig. 7

Axial post-contrastographic T1 3D-weighted images showing diffuse leptomeningeal carcinomatosis in a patient affected by melanoma (a), with bilateral thickened enhancement of the intracisternal segment of the III (b. arrowhead), VI (c. arrows), slight of the VI (d. circles), VII–VIII (d. arrows) and mixed nerves (e. arrows)

Some theories on how malignant cells reach the leptomeninges include perivascular, arachnoid venous, choroid plexus hematogenous dissemination, contiguous dural metastases, and bone metastases.

The most common MRI sign of leptomeningeal carcinomatosis is pial and subarachnoid space enhancement (linear 32% and micronodular 54%), which is 9% of the time associated with nodular thickening that involves multiple nerves that are distant from each other and thicken bilaterally [28].

Since leptomeningeal carcinomatosis is prone to form larger deposits in areas of CSF stasis, such as the cerebellopontine angle and the peri-mesencephalic cisterns, cranial nerves III, V, VII, and VIII are especially involved [28], but hypothetically all the CN may be affected.

Finally, a rare condition that may involve cranial nerves is neurolymphomatosis. It accounts for about the 3% of newly diagnosed non-Hodgkin’s lymphoma or leukemia cases [29]. Different manifestations are described, ranging from a painful polyneuropathy involving the cauda equina to cranial neuropathy and painless or peripheral mononeuropathy involving the sciatic nerve [30]. There is a common involvement of III, V, VI, and VII cranial nerves, with a higher incidence of involvement in their cisternal segments [31]. The enhancement of cranial nerves could be thickened or nodular (bilateral thickening pattern) due to the infiltration of tumor cells into the endoneurium and perineurium [32] (Fig. 8).

Fig. 8

Axial T1 FS post-contrast images showing bilateral thickened enhancement of the intracisternal segment of the III (a., arrows), V (b., arrows), I and VII–VIII (c., arrows) pair of cranial nerves in a patient affected by neurolymphomatosis

Infective-related enhancement

Cranial nerve enhancement in infectious disorders may result in different patterns; usually, viral infection leads to a unilateral and linear enhancement, whereas bacterial and fungal infections are more likely to give a thickened pattern due to inflammatory or infectious agent cells. In bacterial and fungal diseases, if the cranial nerve is involved by contiguity, the pattern is usually unilateral; if the CNE is the consequence of a disseminated infection, the pattern is bilateral.

Viruses represent the most common infectious disorders affecting cranial nerves and causing viral neuritis [33,34,35].

The most common viruses causing neuritis and consequently CNE belong to the Herpesviridae family, including, among others, Herpes simplex type 1 virus (HSV1), varicella-zoster virus (VZV), and Epstein–Barr virus (EBV). HSV1 and VZV often remain latent in the geniculate ganglion (CN VII) thanks to their neurotropism. If an event causes their reactivation, facial nerve inflammation occurs with blood-nerve barrier breakdown, resulting in a typical monolateral linear CNE [36, 37]; sometimes trans-neural infection of adjacent nerves may be associated [26]. HSV-1 is considered the main etiological cause of Bell’s palsy [38,39,40] (Fig. 9), while Ramsay Hunt syndrome is caused by VZV reactivation [37]. A slightly different mechanism, probably related to a para-infectious condition rather than a direct viral infection, characterized EBV CN changes that may affect the CN III nerve with the peculiar "shooting star" sign due to the involvement of its root exit zone with adjacent pial enhancement and associated edematous changes in the ventral mesencephalon [41].

Fig. 9

Patient presented with Bell’s Palsy. Axial T1 3D post-contrastographic images showing linear enhancement of the left VII cranial nerve in its geniculate ganglion region (a, arrow), intratympanic (b, arrow), and intramastoid segments (c, arrow)

Bacterial infection is much less frequent, and CN involvement is often the consequence of other infectious diseases left untreated, generally in the middle ear cavity or paranasal sinuses, or disseminated systemic infection [42,43,44].

The mechanisms leading to CNE are different. In tuberculosis, the pathological nerve enhancement appears to be related to ischemia secondary to vasculitis or nerve entrapment by the exudates from the basal cisterns [15, 45], and therefore, it usually appears as bilateral and thickened, involving CN in their cisternal segments. In Lyme disease, cranial nerve involvement may be related to different processes, such as direct spirochetal invasion [46], vasculitis [16], or an immune-mediated condition [47] usually involving multiple cranial nerves with a bilateral thickening pattern (Fig. 10).

Fig. 10

Axial T1 3D post-contrastographic weighted images show a thickened and asymmetrical but bilateral pathological enhancement of the III (a, arrows), V (b, arrows), VI (c, circles), VII–VIII (c, arrows), IX–X (d, arrows) and of the XII (f, arrows) pair of cranial nerves in a patient affected by Lyme disease

Also, in neurosyphilis infection, multiple cranial nerves are involved, and inflammation could represent the cause of the loss of BNB structural integrity [48,49,50] (Fig. 11). The central nervous system infection in Gradenigo's syndrome, also known as petrous apicitis and frequently caused by Pseudomonas and Enterococcus, is caused by contiguous infective dural invasion, which results in unilateral and thickened enhanced CN V and VI. The classic triad of symptoms is represented by suppurative otitis media, pain in the distribution territory of the trigeminal nerve, and abducens nerve palsy [51].

Fig. 11

Axial T1 3D post-contrastographic weighted images showing bilateral linear enhancement of the III (a, arrows), and V (b, arrows) pair of cranial nerves and of the left VI CN (c, circle) and the right VII–VIII CN (c, arrow) in a patient with neurosyphilis

Finally, fungal infections, such as aspergillosis and mucor mycosis, are particularly prone to perineural involvement; in particular, mucor mycosis presents with a thin and unilateral pattern of cranial nerve enhancement; however, its pathogenesis is not well understood [52]; it could be possibly related to meningeal enhancement or to the presence of phlegmonous soft tissue along the cranial nerve [40]. Infection commonly begins in the paranasal sinuses and then spreads in the intracranial compartment along nerves and adjacent structures, being the CN II and the CNs, into the cavernous sinus [53]. If signal alterations extend posteriorly in the area of the maxillary sinuses, they may mimic the appearance of perineural spread along the V2 segment, and if the infra-temporal fossa is also involved, it could be mistaken for perineural spread along the V3 distribution.

Inflammatory and immune-mediated related enhancement

Inflammatory and immune-mediated diseases can be related to different patterns of CNE due to different pathogenic mechanisms, which are most of the time still not clear. Usually, the pattern is thickened when inflammatory and granulomatous infiltrates are present, whereas it is linear if related to a demyelinating process in the acute phase. It is difficult to label them by location, as, with some exceptions, they can present with both a unilateral and bilateral pattern.

Demyelinating disorders

CNE is often related to an immune-mediated disorder. In this group, the cranial nerve most frequently involved is the II pair with the typical optic neuritis (Fig. 12). Radiologically, optic neuritis is characterized by an acute swelling and enhancement of the optic nerve, usually monolateral, in a short segment if related to multiple sclerosis (MS) or bilateral and longitudinally extensive if related to neuromyelitis optica (NMO) or anti-MOG encephalomyelitis. The involvement and consequently enhancement of the optic nerve in demyelinating spectrum disorders is easily explained by its diencephalic origin and oligodendrocyte myelination, which make it an extension of the central nervous system. In contrast, it is more difficult to explain the enhancement of other cranial nerves in MS that, even if rare, may occur (Fig. 13). It has been hypothesized that anterograde trans-synaptic neurodegeneration or inflammatory extension is a pathogenic mechanism, supported by the fact that, for example, the V cranial nerve enhancement is usually next to a lesion in the pontine entry zone of the trigeminal root [13, 54, 55].

Fig. 12

A case of a patient affected by multiple sclerosis with acute optic neuritis. A Axial FLAIR-weighted image showing multiple sclerosis-related hyperintense lesions in the periventricular white matter. B Coronal STIR-weighted image showing oedematous appearance of the left optic nerve in its intraorbital retrobulbar segment (arrow). That shows linear enhancement after contrast medium administration in c coronal T1 FS post-contrastographic weighted image (arrow)

Fig. 13

A Axial T1 3D post-contrast image showing a slight linear enhancement of the left VII–VIII cranial nerves in the internal acoustic canal (arrow), in a patient affected by multiple sclerosis with lesions in supratentorial (b. axial fat sat FLAIR) and subtentorial (c. axial Fat sat FLAIR) white matter

Guillain–Barré syndrome

Guillain–Barré syndrome and its variant, the Miller-Fisher syndrome, can show cranial nerve involvement, which is clinically associated with ophthalmoplegia, ataxia, and areflexia [56]. The CNE, characterized by a prevalent bilateral thickened pattern, is the result of an immuno-inflammatory process caused by complement activation that leads to an anti-ganglioside antibody-mediated neuropathy [57].

Tolosa–Hunt syndrome

Tolosa–Hunt syndrome is a granulomatous inflammatory disorder of the cavernous sinus that also affects the orbit and superior orbital fissure. Retro-orbital pain and ophthalmoplegia, which may clinically resemble migrating ophthalmoplegia, define this syndrome.

The involvement of the cranial nerves is thus related to the presence of inflammatory tissue that invades the orbital apex with subsequent thickening and ipsilateral enhancement of the optic, oculomotor, and ophthalmic branches of the trigeminal nerve. On MRI, it is possible to observe an abnormal increase in soft tissue in the ipsilateral cavernous sinus [23, 58] (Fig. 14).

Fig. 14

Axial (a) and coronal (b, c) T1 Fat Sat 3D post-contrastographic weighted images, showing a pathological enhancing tissue occupying the right cavernous sinus (a, b arrow), the right superior orbital fissure (a, c circle) and the right orbital apex (a, arrowhead) in a patient with Tolosa–Hunt Syndrome

Ophthalmoplegic migraine

Ophthalmoplegic migraine is a rare syndrome characterized by head pain and ophthalmoplegia. Nowadays, it seems that it not a migraine variant but rather a form of cranial neuropathy that triggers headaches secondarily. The third cranial nerve is most affected by thickening of its cisternal portion. A proposed pathogenetic hypothesis is related to a demyelinating neuropathy; however, the exact pathologic mechanism is still unclear [22].

Sarcoidosis

Sarcoidosis is a chronic systemic disease of still unknown etiology. It is characterized by the presence of non-caseous granulomas, which may infiltrate different organs, including the CNS, with cranial nerves as the most involved site [59, 60]. All the cranial nerves can be involved; however, the most affected are the CN II and VII–VIII, often with unilateral enhancement, but in 30% of cases it can be bilateral [61, 62] (Fig. 15). The underlying pathogenesis of nerve enhancement and thickening is not clear; nevertheless, several theories have been proposed, including epineural or perineural granulomatous inflammation of the extra-cranial portion of the nerve or leptomeningeal granulomatous inflammation with consequent secondary compression and neural suffering [61, 63].

Fig. 15

Axial FLAIR images (a, b) show marked hyperintensity of the region of the optic chiasm (arrowhead), involving the optic tracts (arrows) and extending into the right temporal lobe (asterisk) in a patient with neurosarcoidosis. This finding is correlated with a pathological bilateral thickened enhancement of the intracranial segment of the optic nerves (c, arrows) and of the optic chiasm (d, arrow)

Wegner’s granulomatosis

Granulomatosis with polyangiitis, or Wegener's granulomatosis, is a systemic autoimmune disease characterized by the presence of non-caseous granulomatosis, which generally involves the kidneys and respiratory system [34, 64]. CNS involvement is infrequent, manifesting mainly with pachymeningitis and cranial nerve palsies, which appear thickened on imaging unilaterally or, more often, bilaterally [