Brainstem ischemic syndrome in juvenile NF2

Clinical data

A 25-year-old woman with a history of strabismus surgery in childhood developed episodes of vertigo. After 6 months of persistent symptoms, imaging revealed bilateral vestibular and other cranial nerve schwannomas, multiple meningiomas and a cervical cord ependymoma, as well as several small focal white matter lesions in the corona radiata. There was a subtle, nonenhancing focus of T2-weighted hyperintensity in the L middle cerebellar peduncle on a December 2015 MRI, adjacent to a subsequent area of restricted diffusion (figure 1). There was no family history of NF2, although the parents were not tested or imaged. Single gene testing of blood lymphocytes detected a germline NF2 variant, c.288_290delCTT, which deletes a highly conserved proline residue and is thought to inactivate merlin. A large left lumbar schwannoma raised concern for malignant peripheral nerve sheath tumor and was partially resected via an abdominal approach. There was substantial blood loss requiring transfusion and volume support. Ten days later, she developed progressive slurred speech, left facial numbness, bilateral hand weakness, and difficulty walking. Blood pressure and serum sodium were normal. She progressed to a locked-in syndrome over 4 days with some residual eye movements. Serial MRIs revealed a multifocal, bilateral, spreading area of markedly hypointense apparent diffusion coefficient (ADC) signal (0.3 × 10⁻³ mm²/s) in the pons and left middle cerebellar peduncle (figure 1). At the site of the prior T2 signal change in the left middle cerebral peduncle, there was subtle enhancement where ADC was less decreased. Vascular imaging, including CT angiogram and a catheter angiogram, showed a basilar artery diameter of 3.9 mm at the mid pons and a basilar bifurcation at the level of the dorsum sellae (figure 2, A and B) and was midline throughout, thus not meeting a definition of dolichoectasia.^7,–,9 The anatomy of the basilar artery did not change as seen 5 years later on the 2020 MRI study. Serial ADC maps showed prolonged loss of signal over time rather than the typical phasic pattern seen after ischemic stroke. Perfusion maps suggested decreased cerebral blood volume and cerebral blood flow in the lesion (data not presented). CSF showed a WBC of 5 cells per mm³ but was otherwise normal including nucleic acid amplification tests for viral infection. Biopsy of the left middle cerebellar peduncle in the area of initial enhancement revealed white matter, which varied from near-normal to necrotic. Within the latter, there was evidence of axonal swelling, mild macrophage infiltration, and scant lymphocytes. Luxol fast blue–Periodic acid–Schiff stain showed focal loss of myelin staining but with some fragments showing normal myelin. No vascular pathology was identified. PCR analysis of tissue for infection was negative. Fluorodeoxyglucose-PET 1 month after the onset showed hypometabolism in the pons. Subsequent MRIs demonstrated some persistent restricted diffusion as well as encephalomalacia of the basis pontis and rapid growth of multiple NF2-related tumors. Four years later, the patient is locked-in except for upgaze and is deaf in both ears. A mammalian target of rapamycin inhibitor was started in an attempt to suppress further growth of the tumors.^10,11

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Figure 1 Radiographic features of the case

(A) Aggressive growth pattern of tumors. Note the enhancement in the left middle cerebellar peduncle on August 12, 2016, in the region of T2-weighted signal change. (B) T2 fluid attenuation inversion recovery changes across time. The earlier lesion in 2015 has enlarged and shows enhancement. Biopsy in this region showed necrosis but was negative for tumor or infection. (C) Time course of spreading ADC changes. The duration of depressed ADC is atypically long compared with the phasic pattern usually seen in acute stroke. ADC = apparent diffusion coefficient.

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Figure 2 Vascular imaging

(A) Diameter of the basilar artery at mid pons. The maximal diameter of 3.9 mm did not meet the 4.5-mm threshold for dolichoectasia. The course of the basilar artery was midline. (B) Tip of the basilar artery. The basilar artery bifurcated at the level of the dorsum sellae and thus did not meet the criteria for elongation. Note the persistent right fetal posterior cerebral artery.

Syndrome features

Table 1 shows the findings of 8 cases with regard to 16 predetermined categories of clinical, imaging, genetic, and pathologic features.^3,–,6 In addition, a 2019 article from a UK group described 2 pediatric patients, without clinical details, who had pontine infarcts. One had renal artery stenosis and coarctation of the aorta, and a second had vertebral artery stenosis and a 22q microdeletion.¹² Table 2 shows an analysis of the NF2 variants reported in each case. Overall, the similarities between cases are striking.

To summarize the data, the syndrome of brainstem necrosis in juvenile NF2 typically occurs in teenagers without previously known NF2 as an acute, typically monophasic event in the midbrain or pons. Some patients have had a recent hypoperfusion event. MRI shows markedly restricted diffusion in the lesion, but vascular imaging is normal. Our case demonstrated evolution of imaging findings and showed some unusual features compared with acute stroke. NF2 imaging features are apparent at the time of diagnosis. Typical null NF2 alterations are seen, and absence of family history in most cases suggests a de novo mutation. Biopsy in 2 cases, including ours, shows necrosis without small vessel pathology. The early-onset, high number of NF2-related lesions at diagnosis and the subsequent rapid growth suggest an aggressive form of NF2 in these patients as is often seen in younger patients.