Subacute diencephalic angioencephalopathy: biopsy diagnosis and radiological features of a rare entity

Clinical Neurology and Neurosurgery 103 (2001) 160– 167 www.elsevier.com/locate/clineuro

Subacute diencephalic angioencephalopathy: biopsy diagnosis and radiological features of a rare entity Tarik Tihan a, Peter C. Burger a,b, Martin Pomper c, Oscar Sanchez f, Muhammad Ramzan f, Charles G. Eberhart a, Calvin Hansen d, Thomas W. Smith e,f a

Department of Pathology, Room 713, Pathology Building, Johns Hopkins Uni6ersity School of Medicine, 600 N Wolfe Street, Baltimore, MD 21287, USA b Department of Neurosurgery, Johns Hopkins Uni6ersity School of Medicine, Baltimore, MD 21287, USA c Department of Radiology, Johns Hopkins Uni6ersity School of Medicine, Baltimore, MD 21287, USA d Department of Neurology, Iowa Methodist Centre, Des Maines, IA, USA e Department of Neurology, Uni6ersity of Massachusetts Medical School, Worcester, MA, USA f Department of Pathology, Uni6ersity of Massachusetts Medical School, Worcester, MA, USA Received 2 February 2001; received in revised form 22 May 2001; accepted 22 May 2001

Abstract Subacute diencephalic angioencephalopathy (SDAE) is a rare and fatal disease of unknown etiology that involves the thalami bilaterally. To date, there have been four cases reported, in which the diagnosis was established only after post mortem examination of the brain. We report two male patients, ages 69 and 41 years, who presented with progressive dementia and somnolence. Radiological evaluation revealed enhancing lesions involving both thalami. The differential diagnosis included a number of neoplastic, inflammatory and vascular processes. In both cases, pathological evaluation of biopsy specimens suggested the diagnosis of SDAE. Despite supportive care, the disease progressed rapidly and both patients died within weeks after initial presentation. The diagnosis was confirmed at autopsy in both cases. SDAE is a rare cause of bithalamic disease that can be mistaken for a neoplasm as well as a number of conditions that necessitate different treatment choices. The histopathological findings can establish the diagnosis when combined with radiological and clinical information. This report emphasizes the utility of stereotactic biopsy in early diagnosis of SDAE. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Angioencephalopathy; Dementia; Thalamic degeneration

1. Introduction Bithalamic pathological processes are often characterized by significant impairment of awareness and intellect, leading to profound dementia [1]. The differential diagnosis of dementia with associated bilateral thalamic lesions includes infarctions [2,3], vascular malformations [4,5], tumors [6,7], infections [8], fatal familial insomnia [9,10] and conditions concurrently affecting the cerebral cortex, such as Creutzfeldt – Jakob 

Presented in part at the 76th Annual Meeting of the American Association of Neuropathologists, Atlanta, GA, June 2000. * Corresponding author. Tel.: + 1-410-955-8378; fax: + 1-410-6149310. E-mail address: [email protected] (T. Tihan).

disease [11]. In addition, there are reports of bilateral thalamic disease resulting in dementia that cannot be classified under any of the above categories [12]. The pathological features of this ‘primary’ thalamic dementia include neuronal loss and gliosis without evidence of parenchymal necrosis and a normal cerebral vasculature [13]. DeGirolami et al. described a 60 year old male with exclusively bilateral thalamic involvement, fatal outcome and pathological characteristics consisting of vascular thickening, parenchymal necrosis and gliosis. They suggested the term ‘subacute diencephalic angioencephalopathy’ (SDAE) for this hitherto undescribed entity [1]. We were able to identify three subsequent reports that are consistent with their original description [14 –16]. The diagnosis of SDAE was

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2.1. Clinical course

2.1.2. Case 2 A 41 year old male presented with a 3-week history of unusual behavior, sleepiness and memory loss. The symptoms began 1 week after a fall on ice that did not involve a direct injury to the head. On initial examination, he showed blunted affect, poor short-term memory and mild left central facial paresis. Admission CT scan and MRI evaluation revealed bilateral thalamic lesions (Fig. 2A) that were almost symmetrical, hyperintense on FLAIR and did not enhance or exert mass effect (Fig. 2B,C). A stereotactic biopsy of the posterior right thalamus showed acute neuronal necrosis, gliosis and a necrotizing microangiopathy. The possibility of SDAE was raised based on clinical and pathological findings. Extensive evaluation (including CSF analysis) for possible infectious, hematologic, metabolic and

2.1.1. Case 1 A 69 year old, right-handed male was admitted to the emergency room after a motor vehicle accident. He had sustained sternal and lumbar fractures, but there was no direct injury to the head. He was hospitalized for 12 days after which he was discharged home in a stable condition. A few days after discharge he began complaining of somnolence, followed by urinary incontinence and confusion. There was significant weight loss and change in his personality, but he did not suffer from weakness or sensory loss. He was readmitted to the hospital and a CT scan demonstrated hypodensities in both thalami. MRI was performed the following day and confirmed the bilateral thalamic lesions, which were hyperintense on T1-weighted images (Fig. 1A). The corresponding FLAIR images demonstrated the bithalamic hyperintensities without significant edema or mass effect (Fig. 1B). The cerebral cortex, brain stem and cerebellum were not significantly involved. There was only minimal contrast enhancement. The cerebral angiogram was unremarkable. The differential diagnosis included vascular, neoplastic (glioma, lymphoma) and inflammatory processes. A small amount of tissue was obtained through an endoscopic procedure from the medial aspect of the lateral ventricle. The intraoperative endoscopic impression was that of a tumor because of the abnormal tissue on the ventricular surfaces of the thalami. The biopsy specimen showed only nonspecific gliosis. The endoscopic biopsy procedure was repeated due to worsening of the patient’s condition. The second sample showed focal necrosis, marked vascular thickening with associated gliosis and raised the probability of SDAE. Numerous laboratory diagnostic tests as well as CSF analysis were negative. Despite high dose steroids and supportive treatment, the patient deteriorated gradually and died 3 months after his initial admission. The total duration of his illness was 14 weeks.

Fig. 1. Case 1: (A) Axial T1-weighted (TR/TE, 600/16), non-contrast image reveals bithalamic hyperintensities compatible with punctate hemorrhages. (B) The corresponding FLAIR (TR/TE/TI, 6000/96/ 1800) image shows more prominent bithalamic hyperintensities. Note the lack of mass effect. The brain stem was not significantly involved and post-contrast images revealed only minimal, patchy enhancement (not shown).

established post-mortem in all three of these cases. The radiological features of SDAE are unclear, since only one of the previous studies included a brief description of the computerized tomographic findings [15]. We report two patients with SDAE who presented with dementia and died within months after admission to the hospital. In both cases, the diagnosis was suggested by the pathological findings in stereotactic biopsy specimens and was confirmed at autopsy. The pathological features as well as MRI findings of these unusual cases are presented.

2. Cases

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Fig. 2. Case 2: (A) Axial FLAIR (TR/TE/TI, 9002/142/220) image reveals bithalamic hyperintensities. Note the absence of mass effect. The brain stem was minimally involved at this time (not shown). (B,C) Axial FLAIR (9002/142/220) images : 6 weeks later show extension of the bithalamic process with prominent involvement of the brainstem. The focus of marked hyperintensity in (B) within the right thalamic hemisphere was due to a previous biopsy (arrow).

toxic etiologies was unrevealing. A subsequent MRI study showed progression of the thalamic lesions to the midbrain and pons. Cerebral angiography was performed to exclude vasculitis and revealed an enlarged meningohypophyseal trunk supplying a dural arteriovenous malformation in the right paramedian posterior fossa and several dilated superficial veins (not shown).

The patient subsequently developed Parkinsonian symptoms and his condition progressively worsened during the 2 months of hospitalization. Treatment with steroids and heparin/warfarin anticoagulation therapy provided transient abatement of symptoms. He was discharged home and died 2 months later. The total duration of his illness was 24 weeks.

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2.2. Pathological findings 2.2.1. Case 1 The microscopic findings in the initial biopsy were limited to a non-specific, mild gliosis. The subsequent biopsy demonstrated necrotic parenchyma with gliosis and marked thickening of the small arteries and arterioles. Some of the small arterioles exhibited endothelial hyperplasia and luminal compromise. Parenchymal calcifications were noted. There was marked gliosis and focal areas of rarefaction. At autopsy, the brain weighed 1400 g. The diencephalic lesions consisted of areas of softening with granular texture extending to the pulvinar bilaterally. The changes were more pronounced on the right thalamus. A similar but less pronounced change was present at the periaqueductal region rostrally. A small hemorrhagic focus consistent with the previous stereotactic biopsy was noted within the thalamic lesion. On coronal sections, the lesions were limited to the thalamic gray matter and the periaqueductal rostral midbrain. The basal ganglia and the deep white matter were uninvolved. The arteries of the circle of Willis showed minimal atherosclerosis without luminal compromise. There were no other pathological findings within the meninges or remaining brain parenchyma. No vascular malformation was identified. Microscopically, the sections from the diencephalon demonstrated rather symmetrical, patchy necrosis with prominent dystrophic mineralization, neuronal loss, spongiosis and gliosis (Fig. 3A). Many of the small- to medium-sized vessels were thickened (Fig. 3B). There were occasional macrophages and scattered hemorrhagic foci in addition to the hemorrhages associated with biopsy sites. Smaller vessels in the same region showed hyalinization without mural necrosis, which was also demonstrated on histochemical stains. In some areas spongiotic change was prominent (Fig. 3C). There were scattered inflammatory cells, but no evidence of active vasculitis or encephalitis. The vessels outside the thalamic regions showed no pathological changes. There was no evidence of trauma or contusion. 2.2.2. Case 2 The microscopic examination of the stereotactic biopsy showed necrotic neurons, prominent vascularity, gliosis and somewhat spongy neuropil. At autopsy, the brain weighed 1540 g. There were slightly enlarged and congested vessels in the occipital region. On coronal sections, the changes were identical to those in Case 1, i.e. diffuse softening, yellow-gray discoloration and ‘granularity’ in both thalami and also in the rostral midbrain. The yellow-gray discoloration with a granular and microcystic consistency was observed throughout both thalamic gray matter (Fig. 5). The internal cerebral veins on the surface of the thalami

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appeared pale and prominent. A small hemorrhagic focus compatible with the previous stereotactic biopsy was evident in the right posterior thalamus. In contrast to Case 1, the above changes extended to involve a small portion of the right lateral geniculate body, the pons and medulla oblongata. The gray-white matter distinction was attenuated in the basis pontis. A 1-cm cavitary infarction was present in the left medial cerebellar cortex in the territory of the posterior inferior cerebellar artery. The remainder of the cerebral parenchyma, the spinal cord and the meninges were unremarkable with normal vascular structures. As in Case 1, the histopathological process was characterized by multiple discrete areas of parenchymal necrosis with dystrophic calcifications, neuronal loss, vacuolar change (spongiosis), gliosis, intraparenchymal and perivascular microscopic hemorrhages (Fig. 4A). The vascular changes involved endothelial proliferation in the small- to medium-sized vessels, as well as thickening of vascular walls and scattered dilated vessels with reactive endothelial cells (Fig. 4B). Rare vessels contained fibrin thrombi, but there was no evidence of active vasculitis or encephalitis (Fig. 4C). An increased collagen deposition was noted in some vessels, which could be demonstrated by histochemical stains as well as antibodies for type IV collagen and laminin. Neuronal loss was patchy and axonal swellings were present. The process involved thalami as well as tectum, tegmentum pontis and rostral medulla oblongata. A left cerebellar cavitary infarct was also documented microscopically. Sections from all cortices, basal ganglia, hippocampi and centrum semiovale were histologically unremarkable.

3. Discussion This study describes the radiological and pathological features of two patients with SDAE, a rare disorder of unknown etiology. The features in both cases were progressive mental deterioration, occurrence in adult males, bilateral parenchymal and vascular changes within the diencephalon. The disease has proven fatal in all cases (Table 1) [1,14– 17]. Radiologically, lesions in both of our patients were bilateral, irregular, low-density areas on CT scan and variable contrast enhancement. The MRI imaging features of SDAE were virtually indistinguishable from bilateral thalamic glioma or ischemic/hemorrhagic lesions that have been described in this region [18]. Clinically, SDAE is similar to a group of lesions reported as primary thalamic dementia [12,19,20]. However, such lesions demonstrate changes elsewhere in the central nervous system in addition to the diencephalon, exhibit a more protracted course [12]. Pathologically, the lesions are restricted to specific thalamic nuclei and lack the prominent vasculopathy of SDAE. The vascular changes and parenchymal necrosis seen in

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cases of SDAE are not observed in primary thalamic dementia. Both of our patients had a history of trauma, but there was no evidence of trauma in the CNS including axonal or neuronal damage, even though one cannot entirely exclude the possibility that trauma may have contributed to the disease. Nevertheless, the lesions do not conform to a specific vascular or geographic distri-

bution compatible with a trauma and thick, hyalinized vessels, and tissue calcifications imply a more protracted process than that caused by a recent trauma. The cause of the vasculopathy in SDAE is unknown. Schmidbauer et al. have pointed out the similarities in SDAE to Foix–Alajouanine disease, a spinal cord affliction with pathological features of a malformation [16]. This raises the possibility that the pathological

Fig. 3. Case 1: (A) Histological sections from the diencephalon demonstrating thickened vessels, patchy necrosis with prominent dystrophic mineralization and parenchymal microhemorrhages (H&E original magnification × 100). (B) The area showing marked neuronal loss, spongiotic change and gliosis (H&E original magnification × 200). (C) A medium sized parenchymal vessel showing marked mural thickening and hyalinization. The surrounding parenchyma showing marked gliosis (H&E original magnification ×200).

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Fig. 4. Case 2: (A) Histological section showing discrete areas of parenchymal necrosis with dystrophic calcifications, vacuolar change (spongiosis) and marked vascular thickening (H&E original magnification × 100). (B) Higher magnification showing parenchymal hemorrhage, marked gliosis, neuronal loss and mural thickening of small caliber vessels (H&E original magnification ×200). (C) Rare vessels containing fibrin thrombi without evidence of active vasculitis. The parenchyma shows vacuolar change and gliosis (H&E original magnification ×100).

changes may be due to disturbed venous flow and congestion in the diencephalon [15]. It is, however, difficult to explain how this could produce such devastating bithalamic disease. One of our patients and another previously reported patient with SDAE had small arteriovenous malformations, which have led some to postulate a relationship between two lesions. This suggestion is also supported by the case reports of vascular malformations that lead

to dementia [4,5]. However, the small dural vascular malformation in our case was remote from the thalamic venous drainage bed and we are unable to find any evidence of venous congestion or venous pathology elsewhere. Bilateral T2 hyperintensities within the thalami may be associated with several entities. One, arteriosclerosis in the posterior circulation, may produce ischemic foci within the thalami, but this chronic process usually

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Fig. 5. Case 2: Coronal section of the brain from Case 2. Both thalami display a variegated, dusky yellow-gray discoloration and softening. There are dark areas of granular texture in the left thalamus and in the periventricular gray matter. There is no grossly discernible distortion of the overall architecture. No other lesions are identified elsewhere. Table 1 Subacute diencephalic angioencephalopathy cases in the literature Reference

Age

Sex

Signs and symptoms

Duration (weeks)

Outcome

DeGirolami et al. [1] Kinney et al. [14] Nakada et al. [15] Schmidbauer et al. [16] Case 1 Case 2

60 68 63 58 69 41

M M M M M M

Confusion, dementia, disorientation Progressive dementia, lethargy Confusion, disorientation, ataxia Dementia, hallucinations, motor impairment, spasticity Somnolence, incontinence, confusion, weight loss Behavioral changes, somnolence, memory loss

5 7 7 14 14 24

DOD DOD DOD DOD DOD DOD

results in lacunae. The other major consideration is a bilateral infiltrating glioma, which occurs predominantly in children and often associated with mass effect, which may be slight in some cases [21]. Basilar meningitis associated with bithalamic infarcts has been reported in two patients [18], but similar inflammatory changes have not been noted in SDAE. Other infrequent causes of bithalamic infarcts include Fabry’s disease [22] and the use of oral contraceptives [18]. Some bithalamic infarcts, particularly those due to venous occlusion, may mimic tumor [23]. Occasional patients with prion disease have bilateral thalamic involvement, but the vascular changes, dystrophic calcifications and parenchymal necrosis seen in all cases of SDAE are not encountered in prion diseases [10]. In summary, SDAE is a progressive, fatal disease that presents with dementia and is characterized by bilateral diencephalic parenchymal necrosis, neuronal loss, gliosis and vascular changes. The lesion has affected the brainstem in four of the six reported cases.

The cerebral cortex has been spared. Although there is no known effective therapy, recognition of clinical, radiological and pathological features of the entity may permit an ante-mortem diagnosis and relieve concerns that a treatable entity was overlooked.

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