Neuro Behcet's Disease

Types of NBD

NBD is sub-classified into two major forms: parenchymal and non-parenchymal. The two types rarely occur in the same individual and their pathogeneses are probably different (7).

A. Parenchymal NBD
The parenchymal form of NBD is characterized by focal or multifocal involvement of the brain parenchyma. It is the most common presentation reported in NBD (11), comprising 81% of cases in a study of 200 NBD patients (7). This form of NBD commonly presents with an attack of hemiparesis, cognitive changes, sphincteric troubles and possible fever in men in their third decade. The most common clinical findings are pyramidal tract and brain stem signs. An acute attack may be followed by a relapsing or progressive course (2, 7).

MRI findings in parenchymal NBD: MRI is the most sensitive imaging modality for assessing patients with NBD (18); it shows focal or multifocal CNS abnormalities in the clinically affected areas (17, 19, and 20). The distribution and the MRI signal behavior of parenchymal NBD lesions will be reviewed.

Distribution of parenchymal NBD: Lesions in parenchymal NBD are located in the brainstem, thalami and basal ganglia. However, it can also involve the cerebral hemispheres, cerebellum, spinal cord, and other sites.

Brainstem-thalamic-basal ganglia: Parenchymal NBD lesions have predilection to the brainstem-thalamic-basal ganglia region (Fig 1). They characteristically involve the junction of midbrain and thalamus (meso-diencephalic junction) (Fig 2). The reason for this predilection is unknown (10, 21, 22, and 23). Extensive large lesions are commonly seen in these regions during acute attacks (7).
In the brainstem, the midbrain is most commonly affected site (Fig 3), with the cerebral peduncles involved and the red nuclei characteristically spared (17). The next most common location is the ponto-bulbar region (7, 22), with lesions that usually involve the basis pontis (Fig 4) and occasionally extend to brachium pontis (17, 19, 20, and 21). Although the white matter is more often involved in NBD, lesions may also be seen within the grey matter structures, including brainstem nuclei, cortex and basal ganglia (21, 24). Figure 5 shows symmetrical involvement of midbrain colliculi in parenchymal NBD. The disease commonly involves the basal ganglia and internal capsule region unilaterally (Fig 6), or bilaterally in one third of the cases (7). The globus pallidus and adjacent internal capsule is the most common site affected in this region (Fig 7) (10, 22).
High linear signal intensity in T2 weighted images along the posterior limb of the internal capsule is highly suggestive of NBD (Fig 8). This sign can be seen unilaterally or bilaterally with variable symmetry and severity (7, 22, and 23).
Lesions located in the basal ganglia regions tend to extend caudally along the corticospinal tracts (Fig 9). High signal intensity changes may thus be seen in the fiber tracts of the brainstem and may further extend to the cervical cord (Fig 10). The reversibility of signal changes along this pathway in follow-up MR studies is suggestive that they may represent edema (22). However, in chronic NBD cases, non-reversible signal changes in this distribution can be attributed to wallerian degeneration of the tracts documented in pathological studies (16, 24).

Hemispheric lesions: In sub-acute NBD (a few months after an acute attack,: during either remission or progressive worsening of an acute attack), hemispheric lesions may be seen concomitant with brainstem-thalamic-basal ganglia lesions (7). Hemispheric lesions of NBD are usually subcortical rather than periventricular (Fig 11) (25). However, extensive periventricular white matter changes have been reported (Fig 12) (19, 20, and 26).

Other brain lesions:Cerebellar lesions are less common in parenchymal NBD (7). However, lesions in the cerebellar white matters are occasionally encountered in parenchymal NBD (Fig 13) (7, 22). Involvement of the cranial nerves, rootlet of the spinal nerves and peripheral nerves is exceedingly rare. Contrary to the common belief, isolated aseptic meningitis is distinctly uncommon in BD. Instead, diffuse meningoencephalitis is common (22).

Brainstem atrophy:In chronic stage of NBD, gliosis and atrophy may occur (19, 23, and 27) with striking involvement of the brainstem (Fig 14). Isolated atrophy of the brainstem with relative sparing of the cerebral cortex, though not very frequent, is characteristic of chronic NBD (26).

Spinal cord:The spinal cord is less commonly involved in NBD compared to brainstem-thalamic-basal ganglia or hemispheric regions. The spinal cord lesions tend to extend over two or more vertebral segments posterolaterally and may involve the cervico-medullary junction (Fig 15) (22).

MRI signal behavior of parenchymal NBD:The parenchymal lesions of NBD are hyper intense on T2-weighted images. High-signal intensity lesions represent demyelination, gliosis or transient inflammation and secondary edema supported by the resolution of MR abnormalities in response to methyl-prednisolone and other immunosuppressive therapies (28). Most lesions are somewhat visible on T1 weighted images, but can be very subtle (Fig 8) (7, 19, 22, 23, and 27). Hypointense lesions on T1-weighted images may be seen in chronic lesions (Fig 7) (17). Fluid attenuation inversion recovery (FLAIR) sequences increase MRI sensitivity for NBD lesions, especially juxta-cortical and periventricular (Fig 16) (19). Some lesions may demonstrate contrast enhancement during the acute or the sub-acute phase that resolves in remissions (22, 30). The area of contrast uptake can be nodular, linear, crescentic or irregular and is usually smaller than 5 mm (Fig 17) (18, 25). These changes likely reflect a breakdown in the blood-brain barrier (18).

Temporal course of MRI lesions in parenchymal NBD: Acute phase: There are extensive large parenchymal lesions with predominant involvement of the brainstem-thalamic-basal ganglia region that tend to enhance in contrast studies (Fig 1).
Sub-acute phase: There is marked regression in the appearance of the lesions seen during the acute phase, while there may be smaller scattered lesions in the cerebral white matters and brainstem-thalamic-basal ganglia regions (Fig 11).
Chronic phase: There is marked reduction in the size of the parenchymal lesions that corresponds to clinical remissions and possible appearance of brainstem atrophy (Fig 18) (7, 27, and 31).

Pathological findings in parenchymal NBD:Autopsy studies and biopsy specimens of parenchymal NBD reveal widespread meningoencephalitis with multifocal necrotic foci that tend to accumulate mostly in the brainstem and basal ganglion region (23, 24). A non-specific inflammatory reaction with peri-vascular neurtorphilic or lymphocytic cuffing is commonly seen (23, 24). Gliosis and inflammatory axonal injury are reported in chronic lesions (Fig 19) (32, 33).
The precise pathologic mechanism of parenchymal NBD lesions has not been established. It has been hypothesized that parenchymal NBD lesions could be venous infarcts (22). This hypothesis needs more pathological support as vasculitis cannot usually be demonstrated within the parenchymal NBD lesions (17, 31-33). The presence of abnormal T-cell lymphocyte function points to a possible aberrant immune response to antigenic components of infectious agents such as Streptococcus species (6, 32 and 33).

B. Non-parenchymal NBD:
In the non-parenchymal group, CNS dysfunction is due to involvement of major vessels (vascular NBD) or rarely aseptic meningitis (7). The vascular form of NBD is more often reported from the Middle East (14, 34) and France (35), and less often from other parts of the world (7, 17) with geographical and ethnic variations in disease expression and severity (36).
Vascular NBD usually affects major intracranial vessels with frequent involvement of the venous sinuses, cerebral veins and less commonly the intracranial arteries (7, 35, 37-39). The rare arterial involvements in NBD include thrombosis and aneurysms of the large cerebral arteries (37, 38). Venous sinus thrombosis is the most frequent vascular manifestation in NBD (35, 40) followed by thrombosed deep and cortical cerebral veins (41). The association of venous parenchymal infarcts with venous thrombosis depends on the efficacy of the collateral circulation within the cerebral venous system. The extensive collateral circulation usually allows for a significant degree of compensation in the early stages of sinus venous thrombosis (42).
Vascular NBD usually manifests with acute neurological attacks. The arterial involvement usually presents with stroke that evolves over several hours (7). Raised intracranial pressure is the main clinical manifestation of venous sinus thrombosis with a spectrum of clinical presentations such as headaches, papilloedema, focal neurological deficits, seizures and coma. However, the clinical diagnosis of acute dural sinus occlusion can be difficult to make and is frequently delayed (42).

MRI findings in vascular NBD: The most common MRI findings in vascular NBD are occlusion of the cerebral venous sinuses without or with venous infarcts (7). MRI in conjunction with MR venography (MRV) is highly sensitive in detecting such lesions (42-44).
Venous sinus thrombosis: MRI findings include:
Direct visualization of a thrombus within the vessel. The increased intensity thrombus, detected on T1- and T2- weighted images, may partially or totally replace the flow void of the normal venous channel (Fig 20) (42).
MR venography (MRV) shows lack or impaired flow in the occluded sinus and identifies venous collaterals (Fig 21) (45, 46).

Venous infarcts: Venous infarcts are characterized by their non-arterial distribution. They involve the white matter and/or the cortical-white matter junction, and are often associated with hemorrhage. Bilateral cerebral involvement can occur, including the superior cerebral white matter of the convexities from superior sagittal sinus thrombosis (Fig 22) or the basal ganglia and thalami from internal cerebral vein thrombosis (41, 42).

Parenchymal versus non-parenchymal NBD:
Differentiating between parenchymal and non-parenchymal NBD has significant diagnostic, pathologic, therapeutic, and prognostic implications. Vascular NBD due to isolated intracranial hypertension and dural venous sinus thrombosis have better prognosis if detected and treated early. Acute lesions of parenchymal NBD can be reversible with appropriate treatment such as corticosteroids (11).
The most common forms of NBD, parenchymal and vascular, are distinguished by their unique clinical presentations, characteristic changes in the cerebrospinal fluid (CSF), and MRI findings. Clinically, the parenchymal form manifests with signs and symptoms referable to the brainstem with pyramidal findings, cognitive impairment, ataxia and sphincter disturbance; while the vascular form usually causes raised intracranial pressure due to occlusion of the dural sinuses or very rarely an arterial stroke. CSF findings are different in both groups. In parenchymal NBD, CSF shows pleocytosis with predominance of polymorphonuclear cells, with or without elevated protein level and rarely positive oligoclonal bands. In vascular NBD, the CSF is usually normal except for elevated pressure (22). Conventional MRI can usually differentiate between parenchymal and vascular NBD. However, in some cases, the differentiation between vascular and parenchymal NBD may be difficult because of the presence of parenchymal lesions in the former or in rare instances the coexistence of the two forms. In such cases, special sequences of MRI, such as diffusion-weighted imaging (DWI) or magnetic resonance spectroscopy (MRS), can provide additional information.