Brainstem encephalitis (BE) or rhombencephalitis refers to a rare infectious/inflammatory disease that affects the rhombular (pons, cerebellum, and medulla) secondary to multiple etiologies and different prognosis. This article summarizes the most common noninfectious causes of BE and their neuroimaging findings.
Behcet's disease
Behcet's disease is a rare form of vasculitis that mainly affects small blood vessels. Typical presentations are oral genital ulcers, uveitis, arthritis, and gastrointestinal manifestations. NeuroBehcet's disease consists of a parenchymal inflammatory syndrome that primarily affects the brainstem and BG. Neuro-Behcet's disease is the most common autoimmune disease with BE, reported in up to 50% of patients with systemic Behcet's disease. The characteristic radiographic finding is T2 hyperintensity with angiogenic edema. T1C+ shows moderate patchy parenchymal enhancement, predominantly in the acute phase of the disease (Figure 1). Lesions are common in the brainstem (most commonly affected), followed by BG, thalamus, and, less commonly, in the subcortical white matter and spinal cord. Neurobehcet's lesions can mimic multiple sclerosis, however, periventricular and corpus callosum interface involvement is uncommon. Optic neuritis is common. In addition, vascular involvement can manifest as intracranial sinus thrombosis.
Figure 1. There were 2 patients with Behcet's disease and BE. In case 1 (A and B), the abnormal signal intensity on FLAIR (A) and enhancement (B) was concentrated on the left side of the medulla oblongata. In the second case (C and D), the signal intensity of T2 pons was abnormal, and the right brain and foot were abnormally enhanced
- Systemic lupus erythematosus (SLE)
SLE is an autoimmune connective tissue disease characterized by autoantibody production and immune complex formation. Laboratory abnormalities include abnormal white blood cell count, presence of antinuclear antibodies, double-stranded (ds) DNA antibodies, anti-smith (Sm), antiribonucleoprotein antibodies, anti-ribosomal phosphoprotein (anti-P), antiphospholipid antibodies, serum complement levels, serum immunoglobulins, and elevated erythrocyte sedimentation rate. SLE involvement of the CNS is collectively referred to as neuropsychiatric lupus and can present with headache, seizures, cerebrovascular disease, psychosis, mood disorders, cranial neuropathy, cognitive dysfunction, altered mental status, myelopathy, and movement disorders. CNS involvement includes supratentorial encephalitis, aseptic meningitis, stroke, demyelination, transverse myelitis, and, rarely, BE (figure 2). Radiographic findings are nonspecific, however, multisystem involvement can guide the correct diagnosis. Acute lesions present with edema, inflammatory infiltrates, and demyelination, T2/FLAIR hyperintensity, T1 hypointensity, which may be punctate or peripherally enhanced, and cytotoxic edema may be present in some lesions, suggesting acute ischemic changes.
Figure 2. There were 2 patients with SLE-induced BE. In the first case (A-D), FLAIR showed abnormal signal intensity and pontine swelling, loss of the fourth ventricle (A), and mild enhancement (B). MRI follow-up 1 year later (C and D) showed intermittent development of T2 (C) and T1 (D) right cerebellar hemisphere and right cerebellar midfoot. IN THE SECOND CASE (E AND F), PUNCTATE ABNORMAL SIGNAL FOCI (E) AND PUNCTATE ENHANCEMENT (F) OF THE UPPER PONS AND CEREBELLAR HEMISPHERES OF FLAIR CLIPPERS WERE ASSOCIATED WITH CHRONIC LYMPHOCYTIC INFLAMMATION (CLIPPERS) THAT RESPONDED TO STEROIDS, AND WAS CAUSED BY PERIVASCULAR AND DIFFUSE PARENCHYMAL T CELL INFILTRATION, BUT WITHOUT DEMYELINATION. Clinical manifestations include brainstem and cerebellar symptoms (ataxia, dysarthria, pseudobulbar effects, facial paresthesias/hypoesthesia, spasticity, and diplopia). MENINGITIS, SIGNIFICANT CONSTITUTIONAL SYMPTOMS (E.G., FEVER, NIGHT SWEATS, WEIGHT LOSS, AND LYMPHADENOPATHY), AND PERIPHERAL NERVOUS SYSTEM INVOLVEMENT ARE NOT COMMON FINDINGS OF CLIPPERS. ON IMAGING, BRAIN MRI OF CLIPPERS BE SHOWED PUNCTATE CURVILINEAR ENHANCEMENT FOCI CENTERED ON THE PONS AND CEREBELLUM (FIG. 3). Most lesions are less than 3 mm. If the lesion is larger than 3 mm, an alternative diagnosis should be considered. The T1 enhancement sequence was the best sequence for the disease, and the brainstem lesions were not visible on the T2 and FLAIR sequences. On SWI, significant veins have been observed in the brainstem and cerebellum. Decreases in CBF and CBV were observed in MR perfusion. In addition to MRI, whole-body FDG-PETCT has been proposed as part of imaging in patients with suspected CLIPPERS. This is especially important to rule out the possibility of lymphoma in these patients. IN CLIPPERS, BRAINSTEM LESIONS ARE EITHER NON-FDG-VIGOROUS OR MILDLY HYPERMETABOLIC ON FDG-PET, WHEREAS BRAINSTEM LYMPHOMA IS USUALLY SIGNIFICANTLY HYPERMETABOLIZED. A rapid response to corticosteroids is diagnostic, and a lack of response to treatment warrants consideration of alternative diagnoses.
Figure 3. CLIPPERS SYNDROME. Punctate foci of high signal intensity in the pons and cerebellar hemispheres on T2 (A) and FLAIR (B) with punctate enhancement after contrast injection (C). The lesion is less than 3 mm
- Multiple sclerosis
Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the CNS, with increasing incidence and prevalence over the past few decades. T2/FLAIR and post-enhancement T1 are the main basis for the diagnosis and management of MS. Typical MS is a FLAIR/T2 hyperintense foci predominantly around the ventricles and at the interface of the corpus callosum. Brainstem involvement is also common. Isolated brainstem and cerebellar MS is challenging and difficult to distinguish from other causes of BE. The presence of a central venous sign has been reported to be a very accurate differentiator of MS lesions from BE of other causes. Typical lesions of the supratentorial, corpus callosum, optic nerve, optic chiasm, spinal cord, etc., are also helpful in diagnosis. In the brainstem, MS lesions are usually located periphery (Figure 4). Sometimes cranial nerve nuclei and nerve root access areas are involved, and specific cranial nerve symptoms such as trigeminal neuralgia or facial spasm may occur.
Figure 4. MS cases with brainstem involvement. FLAIR hypersignal intensity foci of pons and right cerebellar foot. The lesions are located on the surface (A and B). Abnormal signal lesions are seen in the right trigeminal nerve root entrance zone (REZ) (A). Supratentorial lesions are typical of MS with Dawson finger morphology (C) and corpus callosum interface involvement (arrow D) ADEM Acute disseminated encephalomyelitis (ADEM) is another immune-mediated disease of CNS demyelination, occurring primarily in early childhood. ADEM usually occurs two weeks after viral infection or vaccination, and is usually monophasic disease (as opposed to MS). Typically presents with multifocal neurologic deficits, sometimes with a prodrome (fever, malaise, irritability, lethargy, headache, nausea, and vomiting). The clinical course of ADEM usually progresses rapidly, with maximum defects appearing within 2-5 days. Common neurologic manifestations include pyramidal signs, ataxia, hemiplegia, optic neuritis, seizures, and spinal cord syndrome. Respiratory failure can occur secondary to brainstem involvement, but is rare. On MRI, there are usually reversible, symmetrical, and ambiguous T2-FLAIR hyperintense foci involving subcortical and deep white matter, BG, thalamus, brainstem, and cerebellum. Lesions may vary in size from patient to patient. Lesions may show enhancement. In addition, spinal cord injury is seen in one-third of patients. In contrast to MS, lesions are monophasic and synchronous, with no periventricular white matter lesions (Dawson's fingers). In addition, ADEM lesions are often larger and poorly marginal compared to MS. Accurate diagnosis is helpful if brainstem involvement, a consistent clinical history (recent viral infection/vaccination), and the presence of large patchy lesions in the subcortical and deep white matter, BG, and thalamus (Figure 5).
Figure 5. A 24-year-old patient with ADEM. The right cerebellar midfoot and pons have FLAIR hyperintensity foci (A), and deep basal ganglia and periventricular regions are involved (B). The lesion is large and ill-defined (compared to MS). Lesions show mild enhancement of open margins (C and D)
- Neuromyelitis optica spectrum disease
Neuromyelitis optica spectrum disease (NMOSD) is another known autoimmune central nervous system inflammation with demyelination, but the prevalence is 100-fold lower than that of MS. It is a clinical manifestation of optic neuritis and myelitis occurring simultaneously or sequentially. It differs from MS in physiopathology in the presence of serum IgG autoantibodies against astrocyte aquiporin 4 (AQP4) in up to 80% of cases. Most of the traditional immunomodulatory drugs used for MS treatment are ineffective or even harmful to NMOSD, so accurate diagnosis is crucial. In addition to optic neuritis and transverse myelitis, NMOSD can affect the brainstem (usually the posterior brain region), diencephalon, and cerebral hemispheres. Brainstem involvement may manifest as nausea and vomiting, hearing loss, diplopia, vertigo, and facial paralysis. MRI is essential for the diagnosis of NMOSD, especially in seronegative patients. MRI findings are characteristic, although not characteristic, of NMOSD. Classic radiographic findings include unilateral or bilateral optic neuritis and complete transverse myelitis, which occur simultaneously or sequentially at different times. The distribution of lesions on MRI parallels the site with the highest AQP4 expression at any level adjacent to the ventricular system, such as the hypothalamus, the periventricular region of the third and lateral ventricles, the cerebral aqueduct, the corpus callosum, and the dorsal aspect of the brainstem near the fourth ventricle (Figure 6). Diencephaly lesions and abnormal signal lesions on the dorsal aspect of the brainstem, around the fourth ventricle, including the posterior brain region and nucleus solitus, are highly specific for NMOSD. However, lesions are not confined to areas with high AQP4 concentrations. Up to 42% of patients can meet imaging criteria for MS, including corpus callosum involvement. Nonetheless, unlike MS, these lesions are usually located on the ventricles and ependymal surfaces, whereas MS lesions are predominantly located around the ventricles. The involvement of gray matter is also essential to distinguish between MS and NMOSD. Cortical lesions are reported more frequently in MS by using the 7T MR scanner; however, they are rare in NMOSD. Longitudinal generalized myelitis lesions (LETMs) involving 3 or more vertebral segments are thought to be suggestive of NMOSD, typically involving more than 50% of the spinal cord and gray matter surface. LETM is more common in the cervical spinal cord and may involve the brainstem. In contrast, MS spinal cord injuries are usually small and peripheral.
Figure 6. Two cases of NMOSD. In the first case (A-C), there were patchy FLAIR hyperintense foci in the pons, cerebellar feet, and cerebellar hemispheres (A and B), with right posterior optic nerve involvement (arrow C). In the second case, FLAIR hyperintensity foci around the fourth ventricle (D) involved the thalamus (E) and the junction of the pons oblongata and cervical medullary cord (F)
- Anti-MOG-associated encephalomyelitis
Serum immunoglobulin G antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been described for decades. However, its pathophysiology and association with demyelination have not been explained until recently. Anti-MOG antibody-associated encephalomyelitis/encephalitis is now considered a separate demyelinating disease. It is presented in a similar way to ADEM. However, anti-MOG-associated demyelination may recur, and ADEM is usually a monophasic disease. Anti-MOG antibody-associated encephalomyelitis/encephalitis is more common in children. The condition may be similar to NMOSD, and this antibody is positive in 40% of patients with NMOSD who are seronegative for aquaporin 4 (AQP4) antibodies. The neuroimaging findings of anti-MOG demyelination are similar to those of ADEM, with diffuse T2/FLAIR signal abnormalities in cortical gray matter (GM)/subcortical white matter (WM), deep WM, and deep GM. Compared with ADEM lesions, anti-MOG-related changes are clear and cortex-based. The optic neuritis (ON) pattern can distinguish between anti-MOG encephalomyelitis and MS. Anti-MOG-associated ON is usually bilateral and elongates with involvement of the optic nerve orbit, but does not affect the optic chiasm. Perorbital nerve augmentation and orbital tissue extension are also common in anti-MOG-related ON. On the other hand, ON in MS is usually shorter in extension and involves crossing. Also in MS-associated ON, optic nerve enhancement does not extend to adjacent soft tissues. BE can be seen in one-third of patients with anti-MOG-associated encephalomyelitis (Figure 7).
Figure 7. A patient with anti-MOG syndrome involving the ventral medulla oblongata (A) and superior cerebellar foot
- 医脉通编译自：Sotoudeh H, Razaei A, Saadatpour Z, Gaddamanugu S, Choudhary G, Shafaat O, Singhal A. Brainstem Encephalitis. The Role of Imaging in Diagnosis. Curr Probl Diagn Radiol. 2021 Nov-Dec; 50(6):946-960. doi: 10.1067/j.cpradiol.2020.09.004. Epub 2020 Sep 24. PMID: 33032853.