Primary CNS Vasculitis Mimicking Brainstem Encephalitis

Dear Editor,

Brainstem involvement has been described in various pathologies like infections, autoimmune disorders, and neoplasms.[1] Patients with brainstem involvement usually present with multiple clinical features like motor deficits, ataxia, and cranial nerve palsies, which makes early diagnosis challenging. Autoimmune brainstem encephalitis (ABE) can result from primary involvement of the brainstem alone or may be secondary to systemic disease. The common etiologies of the former include multiple sclerosis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis. We describe a case of ABE caused by primary central nervous system vasculitis (PCNSV), which is extremely rare.

A 30-year-old gentleman presented with recurrent focal neurologic deficits for the past 4 years. In the first episode 4 years ago, he had developed acute-onset severe headache associated with vomiting, followed by loss of consciousness and left hemiparesis 3 days later. The symptoms were preceded by a fever prodrome 5 days back and were treated elsewhere as a case of possible meningoencephalitis with broad-spectrum antibiotics and steroids. He regained consciousness over the next 2–3 days and regained baseline status by 1 month. Three years later, he developed another similar episode, also associated with swaying while walking and a seizure. He was again managed along the same lines with an antiseizure medication with incomplete recovery (no improvement in swaying). He presented to us 1 year later with another episode of seizure 2 days back. There was no history of hiccups, vision loss, weakness or sensory loss over the face, altered speech or difficulty in swallowing, joint pains, rash, orogenital ulcerations, or bladder involvement. He had no loss of weight or appetite and did not receive any vaccinations before symptom onset.

Examination revealed mild weakness of the left side (power 4+/5 on the Medical Research Council scale) with 20%–30% sensory loss. He had bilateral cerebellar signs with impaired tandem gait. His deep tendon reflexes were brisk (left > right) with an extensor plantar reflex on the left side.

He was evaluated for a possible recurrent brainstem encephalitis syndrome. His routine investigations (hemogram, liver and renal function tests, lipid and thyroid profile) were nonrevealing. Viral markers for human immunodeficiency virus, hepatitis B and C were negative. Serum venereal disease research laboratory, antinuclear antibody, extractable nuclear antigen, rheumatoid factor, and anti-neutrophilic cytoplasmic antibody were normal. Serum aquaporin 4, myelin oligodendrocyte glycoprotein IgG antibodies, autoimmune and paraneoplastic panels were negative. Testing for human leukocyte antigen-51 was negative.

Magnetic resonance imaging (MRI) of the brain [Figure 1] revealed a decrease in abnormal signal activity and atrophy in the brainstem. T2-weighted and fluid attenuated inversion recovery (FLAIR) images displayed widespread hyperintensity in the white matter. Susceptibility weighted imaging (SWI) images revealed widespread areas of both macrohemorrhages and microhemorrhages. After the administration of gadolinium, there was a dot–linear enhancement pattern throughout the white matter. MRI of the brain of the previous attack was also reviewed and found to have T2 and FLAIR abnormalities in the brainstem, specifically in the pons, extending downward to the medulla and upward to the midbrain and thalami. T2 gradient images revealed a hemorrhagic area within the lesion located in the right half of the pons. No diffusion restriction was observed, and there was patchy enhancement after gadolinium administration, as depicted in Figure 2.

Figure 1.

Axial (a, b) and coronal (c) FLAIR images show pontine atrophy (arrow in a), with hyperintensities in the left temporal lobe (dotted arrow in a), posterior limb of the internal capsule, periventricular (arrows in b), and subcortical white matter. On SWI images (d, h), diffuse microhemorrhages are seen in the pons (arrow in d), cerebellum, and bilateral cerebral hemispheres (arrows in h). In addition, there is a macrohemorrhage in the left occipital lobe (dotted arrow in h). Postcontrast T1-WIs (c) show widespread dot-linear enhancement (arrows) in the brainstem, cerebellum, and both cerebral hemispheres. FLAIR: fluid attenuated inversion recovery, T1-WI: T1-weighted image, SWI: Susceptibility weighted imaging

Figure 2.

Axial T1-WI (a) and T2-WI (b) reveal T1 hypointensity and T2 hyperintensity in the pons, extending into bilateral middle cerebellar peduncles (arrows) with focal CSF intensity (dotted arrow suggesting cavitation/necrosis) in the central pons. Sagittal FLAIR image (c) and coronal T2-WI (d) show hyperintensity (arrows in c, d) extending superiorly to the midbrain and thalami (short arrows in d) and inferiorly to the medulla (dotted arrow in c). No diffusion restriction is seen in DWI (e). T2 gradient image (f) shows hemorrhagic foci (arrow) in the right half of the pons. Axial (g) and coronal (h) T1-WIs show patchy enhancement (arrows) with nonenhancing central necrotic area (dotted arrows) in the pons. FLAIR: fluid attenuated inversion recovery, T1-WI: T1-weighted image, T2-WI: T2-weighted image, DWI: Diffusion weighted imaging, CSF: Cerebrospinal fluid

Cerebrospinal fluid (CSF) examination showed nil cells and normal sugar, but elevated protein levels (182 mg/dl). The remaining CSF investigations including stains and cultures were negative. A possibility of PCNSV was considered based on the clinicoradiologic profile. Digital subtraction angiography (DSA) revealed a pseudophlebitis pattern in both cerebral hemispheres, confirming a high probability of PCNSV [Figure 3]. A brain biopsy was done from the right frontal lobe, which showed granulomatous inflammatory changes, confirming our diagnosis. He was treated with intravenous pulse methylprednisolone (1 g) for 5 days, followed by gradual taper of weight-based oral steroids along with once-a-month intravenous infusion of cyclophosphamide (750 mg/m²) for six doses. He was completely asymptomatic at 1-year follow-up.

Figure 3.

DSA images of the right ICA (a, b) and left ICA (c, d) reveal pooling of contrast in the delayed venous phase of the angiogram (indicated by arrows) within both cerebral hemispheres (resembling pseudophlebitis). No abnormalities are observed in the arterial phase (a, c). DSA: digital subtraction angiography, ICA: internal carotid artery

PCNSV is a rare, heterogenous, inflammatory disorder affecting the small- and medium-sized blood vessels of the central nervous system (CNS).[2] It has a male predilection and it usually occurs in the third to fourth decade.[2] The most common symptoms include headache, focal neurologic deficits, seizures, and cognitive impairment, and isolated brainstem manifestations are rare.[3,4] The diagnosis is based on Calabrese and Mallek diagnostic criteria.[2] Our patient fulfilled the diagnostic criteria based on his clinical symptoms and DSA findings alone. Despite recent advancements in the diagnosis and treatment of PCNSV, definitive diagnosis remains a challenge due to the absence of a highly sensitive or specific noninvasive (serological or radiologic) investigation or finding.[5] Therefore, a brain biopsy (gold standard for PCNSV diagnosis) was done for a definitive diagnosis in view of his atypical presentation. The pseudophlebitis pattern (venous phase abnormality) on DSA is more commonly seen in Indian patients, compared to arterial beading.[6] We also ruled out all other common etiologies of ABE by relevant testing. Patients with vasculitis can have periods of relative quiescence before recurrence, in the absence of treatment. Our patient was relatively normal for 3 years in between his neurologic deficits, proving that a diagnosis of vasculitis cannot be ruled out in such presentations. He responded very well to steroids and cyclophosphamide and continued to be asymptomatic and relapse free at 1-year follow-up, emphasizing the need for early and aggressive management of PCNSV patients. We highlight that PCNSV can present as ABE and should be considered as a cause for the same.

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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.