Neurosarcoidosis Presenting with Prominent Periventricular White-Matter Lesions during Steroid Treatment for Autoimmune Hepatitis.

A 63-year-old woman under treatment of autoimmune hepatitis presented with headache, memory loss, and somnolence. Three months before admission, the patient experienced liver inflammation relapse after prednisolone (PSL) cessation. Consequently, PSL was resumed and then tapered. Cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis with remarkably reduced glucose and elevated angiotensin-converting enzyme and soluble interleukin-2 receptor levels. Magnetic resonance imaging (MRI) revealed prominent bilateral periventricular white-matter lesions, hydrocephalus, ischemic stroke with gadolinium enhancement of frontoparietal and basilar meninges on contrast-enhanced fluid-attenuated inversion recovery. Magnetic resonance angiography (MRA) showed narrowing of the bilateral middle cerebral arteries. Based on these findings, we diagnosed the patient with neurosarcoidosis. Re-increment of PSL improved the neurological symptoms, CSF findings, and abnormalities found on MRI and MRA. This case suggests that neurosarcoidosis may occur as a complication of some autoimmune diseases during immunotherapy administration.

Introduction

Sarcoidosis is a multisystem inflammatory disorder that affects various organ systems. Neurosarcoidosis occurs in 5–10% of patients with sarcoidosis [1]. However, diagnosis of neurosarcoidosis is often difficult due to its diverse clinical symptoms and low sensitivity of ancillary investigations, particularly in cases of isolated neurosarcoidosis. Although the pathogenesis of sarcoidosis has not been fully elucidated, it can develop from autoimmune conditions and is characterized by noncaseating granuloma formation accompanied by aggregation of hypertrophic macrophages and activation of Th1 cells [2, 3]. Herein, we report a case of isolated neurosarcoidosis during tapering of steroid treatment of autoimmune hepatitis (AIH).

Case Presentation

A 63-year-old woman was admitted to our hospital with complaints of headache, memory loss, and somnolence. The patient had been diagnosed with AIH at the age of 58 years. This diagnosis was based on serologic findings, such as increased serum immunoglobulin G levels and positive antinuclear antibody test, and histological findings including interface hepatitis and hepatocyte rosettes formation. However, the patient was successfully treated with prednisolone (PSL). Three months before admission, she experienced liver inflammation relapse after PSL cessation. Therefore, treatment with PSL (20 mg/day) was resumed and then tapered to 10 mg/day. On admission, the patient presented with disorientation and memory loss without signs of meningeal irritation or cranial nerve palsy. Her physical examination revealed body temperature, 36.7°C; blood pressure, 118/82 mm Hg; and pulse rate, 67 beats/min. Laboratory test results were within normal range, except for mild hyponatremia (131 mEq/L). Immunological assessment showed no obvious abnormal findings suggestive of autoimmune disease or vasculitis, except for the presence of the antinuclear antibody (cytoplasmic pattern, 640-fold) and antithyroglobulin antibody (1,146 IU/mL). The serum concentrations of angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL2R) were within normal limits. However, cerebrospinal fluid (CSF) examination detected lymphocytic pleocytosis (94 cells/mm3); remarkably reduced glucose levels (4 mg/dL; blood glucose, 122 mg/dL); and elevated concentrations of protein (1,078 mg/dL), adenosine deaminase (19.5 IU/L), ACE (5.4 U/L), and sIL2R (6,777 IU/L) (Table 1). Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) demonstrated prominent bilateral periventricular white-matter lesions and mild noncommunicative hydrocephalus. Contrast-enhanced FLAIR showed abnormal gadolinium enhancement of the bilateral frontoparietal meninges, basilar meninges, and along the margin of the inferior horn of the lateral ventricle. Diffusion-weighted imaging revealed hyperintense areas in the bilateral basal ganglia, and magnetic resonance angiography (MRA) showed narrowing of the bilateral middle cerebral arteries (Fig. 1a-c). Whole-body contrast-enhanced computed tomography detected no abnormal lesions, including malignancy, tuberculosis, or bilateral hilar lymphadenopathy (images not shown). Based on a tentative diagnosis of bacterial or tuberculous meningoencephalitis, we initiated treatment with meropenem 6 g/day, vancomycin (3 g/day), ethambutol (750 mg/day), pyrazinamide (1,500 mg/day), isoniazid (300 mg/day), rifampicin (600 mg/day), and PSL (60 mg/day: 1 mg/kg/day). Meropenem and vancomycin were discontinued immediately after blood and CSF cultures were negative for bacteria. The patient's neurological symptoms gradually improved. Moreover, on day 30 after admission, CSF and MRI findings improved (Fig. 1d). However, following PSL tapering (10 mg/day), her neurological symptoms recurred, accompanied by a new hyperintense area in the left basal ganglia on diffusion-weighted imaging and exacerbation of hydrocephalus on day 36 (Fig. 1e, f). Immediate re-increment of PSL (40 mg/day) ameliorated the neurological symptoms and CSF and MRI findings. However, mild periventricular white-matter lesions remained. Suspecting neurosarcoidosis, we performed a brain biopsy of the left frontoparietal meninges, excluding periventricular white-matter lesions to avoid neurological complications. We found perivascular infiltration of CD68-positive macrophages without apparent granuloma in the leptomeningeal lesions, which may have been affected by PSL treatment (online suppl. material; for all online suppl. material, see www.karger.com/doi/10.1159/000526223). We discontinued the antituberculosis drugs based on negative results of tuberculosis using an interferon-gamma release assay, CSF culture, and brain biopsy (Table 1). The resultant treatment with PSL alone did not worsen her symptoms and significantly decreased ACE and sIL2R levels in the CSF. Both the hydrocephalus and periventricular white-matter lesions on CE-FLAIR and narrowing of the bilateral middle cerebral arteries on MRA were ameliorated on day 98. Eventually, the PSL dose was tapered to 20 mg/day. The patient was transferred to a rehabilitation hospital with mild gait disturbance (Fig. 1g, h).

Table 1

Laboratory findings on presentation

Complete blood count		Biochemistiy		Serology			CSF analysis
WBC	7,000	/µL	TP	6.7	g/dL	CRP	0.21	mg/dL	Opening pressure	18	mmH20
Neu	69.5	%	Alb	3.8	g/dL	ACE	5.0	U/L	Cells	94	/µL
Eo	0.4	%	AST	10	U/L	sIL2R	432	U/mL	Glu	4	mg/dL
Mo	7.2	%	ALT	10	U/L	Adenosine deaminase	29.2	IU/mL	Protein	1078	mg/dL
Ly	22.6	%	ALP	77	U/L	T-SPOT	(–)		ACE	5.4	U/L
RBC	409 × 104	/µL	γ-GTP	19	U/L	TSH	1.47	µIU/mL	sIL2R	6777	U/mL
Hb	13.4	g/dL	T.Bil	1.2	mg/dL	Free T4	1.22	pg/mL	Lysozyme	16.5	pg/mL
Hct	38.3	%	CPK	20	U/L	ANA	640	Fold	Adenosine deaminase	19.5	IU/mL
Pit	409 × 104	/µL	BUN	20.6	mg/dL	Anti-ds-DNA-Ab	<10	IU/mL	Culture for bacterium	(–)
			Cre	0.57	mg/dL	Anti-CCP-Ab	<0.5	U/mL	Culture and PCR for mycobacteria	(–)
Coagulation		UA		mg/dL	PR3-ANCA	<0.5	U/mL	PCR for herpes simplex virus	(–)
APTT	35.9	s	Na	131.3	mEq/L	MPO-ANCA	<0.5	EU	PCR for varicella-zoster virus	(–)
PT	92	%	K	3.8	mEq/L	C3	116	mg/dL	PCR for cytomegalovirus	(–)
PT-INR	1.0		Cl	93	mEq/L	C4	26.2	mg/dL	Ciyptococcus neoformans antigen	(–)
FDP	<2.5	µg/mL	Ca	9.3	mg/dL	CH50	51	U/mL	Aspergillus antigen	(–)
D-dimer	0.8	µg/mL	Glu	122	mg/dL	Anti-TPO-Ab	<9.0	IU/mL	Cytology class II
			HbA1c	5.4	%	Anti-Tg-Ab	1146	IU/mL	Oligoclonal band	(+)
						β-D glucan	<5.0	pg/mL	IgG index	1.6
						Anti-HIV Ab	(–)		Paraneoplastic antibodies panel*(–)

Paraneoplastic antibodies panel included Amphiphysin, CV2, PNMA2 (Ma2/Ta), Ri, Yo, Hu, recoverin, SOX1, titin, zic4, GAD65, and Tr(DNER).

Fig. 1

aCE-FLAIR on admission shows abnormal gadolinium enhancement of the basilar meninges, along the margin of the inferior horn of the lateral ventricle, and bilateral frontoparietal meninges (yellow arrowheads), as well as mild noncommunicative hydrocephalus (yellow arrows) and bilateral periventricular white-matter lesions (white arrowheads).bMRA on admission reveals narrowing of the bilateral MCAs (yellow arrows).cDWI detects hyperintense areas in the bilateral basal ganglia (yellow arrowheads).dCE-FLAIR on day 30 demonstrates improvement in the previously noted abnormalities related to the hydrocephalus, periventricular white-matter lesions, and gadolinium enhancement of the meninges.e,fCE-FLAIR and DWI on day 36 showed exacerbation of the hydrocephalus (yellow arrows) and periventricular white-matter lesions (white arrowheads) and detects a new hyperintense area in the left basal ganglia (yellow arrowhead).gCE-FLAIR on day 98 shows amelioration of the hydrocephalus, periventricular white-matter lesions, and gadolinium enhancement of meninges.hMRA on day 98 reveals improvement in narrowing of the bilateral MCAs (white arrows). CE-FLAIR, contrast-enhanced fluid-attenuated inversion recovery; DWI, diffusion-weighted imaging; MRA, magnetic resonance angiography; R, right; MCAs, middle cerebral arteries.

Discussion/Conclusion

We diagnosed the patient with neurosarcoidosis that developed during the tapering of steroid therapy for AIH based on the following findings. First, pleocytosis was detected with remarkable reductions in CSF glucose levels without obvious infection. Second, there was remarkable CSF-specific increase in ACE and sIL2R levels. Third, periventricular white-matter lesions with noncommunicative hydrocephalus as well as ischemic stroke were associated with inflammatory spread with leptomeningeal involvement. Fourth, rapid remission occurred after PSL treatment.

Up to 20% of patients with neurosarcoidosis present with remarkable hypoglycorrhachia due to glucose consumption by inflammatory cells such as macrophages and Th1 cells [4]. CSF-specific increase in ACE and sIL2R levels supports the presence of active macrophages and Th1 cells in the brain, in parallel with the disease activity [5]. One of the features of the present case was prominent periventricular white-matter lesions, a common manifestation of neurosarcoidosis [6]. Although no apparent granuloma was detected in the biopsy specimens, we found perivascular infiltration of CD68-positive macrophages (and/or microglia) that may have been affected by PSL administration. We suggest that active macrophages (and/or microglia) along with Th1 cells accumulated and participated in forming periventricular white-matter lesions [7]. Insufficient immunosuppression caused by inappropriate cessation or reduction in the PSL dose may have reactivated these inflammatory cells and worsened the lesions. There have been reports describing development of sarcoidosis following steroid reduction in patients with systemic lupus erythematosus [8, 9].

Recent evidence has demonstrated that vimentin, an intermediate filament protein, can act as an autoantigen in some autoimmune diseases, including sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis, and AIH [10, 11]. Vimentin is highly expressed in the periventricular zone and regulates neural stem cells activity [12]. Vimentin is also produced by hepatic stellate cells and can be a target of antismooth muscle autoantibody-V in type I AIH [10]. Thus, neurosarcoidosis, particularly when it involves the periventricular zone, may share autoantigens with some types of autoimmune diseases. AIH is a major autoimmune disease that can be complicated by sarcoidosis [3]. Furthermore, there have been some reported cases of hepatic sarcoidosis that were difficult to differentiate from AIH [13, 14].

To our best knowledge, this is the first reported case of isolated neurosarcoidosis presenting with prominent periventricular white-matter lesions that developed during tapering of steroid therapy for AIH. Therefore, clinicians should consider the possibility that neurosarcoidosis, particularly involving the periventricular zone, may occur in some autoimmune diseases during immunotherapy administration.

Statement of Ethics

This study was conducted in line with the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors received no funding for any research relevant to this study.

Author Contributions

Conception and design of work, acquisition of data, and interpretation of data: Tomoya Shibahara and Tetsuro Ago; critical revision for important intellectual content: Fumitaka Yoshino, Mikiaki Matsuoka, Masaki Tachibana, Kuniyuki Nakamura, and Junya Kuroda; final approval of the version to be published: Hiroshi Nakane.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

Supplementary data

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