Tumefactive demyelinating lesions (TDL) are defined as solitary intracranial demyelinating lesions more than 2 cm in diameter [1],[2],[3],[4],[5]. Neuroradiology shows low signal on T1-weighted magnetic resonance image (MRI), high signal on T2-weighted MRI, and ring enhancement effect on T1 of gadolinium (Gd) contrast administration [6]. Compared to the size of the lesion, it is characterized by a less compressive effect on the surrounding brain [7]. The incidence of TDL is rare at 0.3/100,000/year, more common in women, and the mean age of onset has been reported to be 37 years [3]. Tumefactive multiple lesions have been reported to be the most common form of TDL in Japan. Among them, tumefactive multiple sclerosis (tMS) is a rare subtype of multiple sclerosis (MS) with TDL, occurring at a frequency of 0.1–0.2% of MS [8]. Focal demyelinating degeneration is the predominant cause. Depending on the site of onset, it can lead to motor paralysis, sensory deficits, higher brain dysfunction, epilepsy, and other disorders. However, the pathogenesis and pathophysiology of tMS remain unclear [9].

In some cases, the diagnosis may be difficult to distinguish from a brain tumor. A definitive diagnosis is usually made by the pathological examination following to the surgical removal of the lesion [7],[10],[11]. Here reports on intraoperative findings that may help to elucidate the pathophysiology of the disease.

A 48-year-old woman presented to the hospital with a headache for several days. She was not accompanied by impaired consciousness (scoring 15 points on the Glasgow Coma Scale: 4 points for eye movement, 5 points for verbal response, and 6 points for motor response), hemiplegia (scoring 5 points for all rims on the Manual Muscle Testing scale), visual field disorder, or higher brain dysfunction (scoring 28 points on the Japanese version of the Mini-Mental State Examination, and 43 seconds for part A and 84 seconds for part B of the Japanese version of the Trail Making Test). Seizure or seizure-like clinical episode was not observed. An MRI scan of the head revealed a 3 cm diameter mass lesion in the right occipital lobe with T1 iso, T2 hypo, flow attenuated inversion recovery (FLAIR) hypo and diffusion-weighted image (DWI) hyper (Figure 1). Gadolinium-enhanced magnetic resonance imaging showed ring-like enhancement (Figure 1). Computed tomography (CT) scan showed iso density, which was surrounded with low density area (Figure 1). Perfusion CT showed that cerebral blood volume (CBV) was unchanged, but cerebral blood flow (CBF) was slightly decreased (Figure 1). Positron emission tomography (PET) scan showed negative in 5-fluorodeoxyglucose (FDG) accumulation (Figure 1) and weak positive in methionine accumulation (Figure 1).

The patient had a mild fever of 37.0 °C and an elevated white blood cell count of 13,470/µL, but there was no evidence of liver or kidney dysfunction. There were no electrolyte or coagulation abnormalities, and the C-reactive protein (CRP) test was negative. Tumor markers were also negative. No significant abnormal findings were noted in the examination of the cerebral spinal fluid (CSF). Subsequently, the patient also complained of disturbance to her left visual field (including transient visual hallucinations and photosensitivity).

Based on imaging studies, glioma, brain abscess, and metastatic tumor were listed as differential diagnoses. However, these diagnoses could not be confirmed through physical and radiological imaging examinations alone. A pathological diagnosis was deemed necessary, so a craniotomy was performed under general anesthesia one month after the initial diagnosis. Using optical navigation system (StealthStation7, Medtronic, Dublin, Ireland) in the park bench position, the lesion was located and the parenchymal portion of the mass was removed. Intraoperative observation under excitation light illumination was found to be positive for 5-aminolevulinic acid (Ala)-induced protoporphyrin IX (PPIX) fluorescence. In order to ascertain the excitation light, the core of the lesion was irradiated with ultraviolet light at a wavelength of 400 nm (Blue 400) under the microscopic view of KINEVO 900 (Carl Zeiss Meditec, Jena, Germany). As illustrated in Figure 2, excitation light induced by 5Ala was observed to be pink in color.

Pathological examination revealed a necrotic lesion with low cell density and inflammatory cell infiltration. Inflammatory cells were predominantly cluster of differentiation (CD) 68-positive histiocytes (Figure 3). Myelin basic protein staining and Kluver–Barrera staining show the demyelinated status (Figure 3). Grocott’s stain showed no evidence of fungal or protozoan infection. Histologically, tumefactive demyelinating lesions (TDL) were suspected. Additional serological tests showed negative in anti-myeline oligodendrocyte glycoprotein (MOG) and anti-aquaporin (AQP) 4 antibodies. A diagnosis of tumefactive multiple sclerosis was made three months after the initial diagnosis.

Treatment with steroids was initiated once the diagnosis had been confirmed. Methylprednisolone sodium succinate was given intravenously at 1 g per day for the first three days. Prednisolone was then taken orally for the following two weeks at 30 mg per day, decreasing gradually. The patient’s residual lesions, including edematous changes, were resolved for 20 days. The patient was discharged home without any neurological complications at five months after the initial diagnosis.

Tumefactive MS is predominantly a focal, central demyelinating lesion, with imaging findings similar to high-grade gliomas [2],[3],[4],[5]. It is characterized by extensive surrounding edema on T2 and FLAIR sequences, and ring-like enhancement on gadolinium-enhanced MRI. However, it usually lack some imaging findings that are typically associated with high-grade gliomas, such as weak methionine accumulation and increased vascularity and blood flow to the lesion on angiography. There may also be a lack of arteriovenous (AV) shunt. There is extensive edema relative to the size of the lesion. Some patients have extensive edema but lack the characteristics of malignancy. These include mild cerebral swelling and peri-brain compression [4]. A diagnosis is often difficult to confirm using preoperative imaging studies alone. The final diagnosis is made by removing and examining the tumor under pathological study.

As far as the author was able to ascertain, no reports focusing on the presence or absence of 5Ala induced PPIX fluorescence were found. However, there are some case reports describing intraoperative fluorescence as either weakly positive [12],[13] or negative [14]. No definitive findings have yet been established.

Five Ala is the enzyme substrate of 5-aminolevulinate dehydratase, which is widely present in various organisms. Five Ala is taken up and degraded in the mitochondria to produce adenosine triphosphate (ATP), which is used as an energy substrate [15],[16],[17],[18],[19],[20],[21],[22]. Protoporphyrin IX, an intermediate product of this degradation process, fluoresces when exposed to excitation light [20],[21],[22],[23]. Since the function of mitochondria is reduced in tumor cells, the intermediate metabolite of 5Ala, PPIX, accumulates. This technique has been applied to the surgical removal of tumors, including glioma, and has contributed to improve therapeutic outcomes [24],[25],[26].

An increase in the fluorescence of 5Ala induced PPIX was observed in tMS tissue. This was thought to be caused by an increase in 5Ala uptake associated with demyelination as well as the accumulation of PPIX due to decreased 5Ala metabolism associated with mitochondrial damage [27].

In rats, it has been reported that loss of mitochondrial function causes demyelination [21]. Under normal conditions, the migration of mitochondria into the axon of the demyelinated area contributes to protection from neurodegeneration [23]. However, in demyelinating diseases such as MS, dysfunction of mitochondria within neurons is observed, which leads to neurodegeneration [28].

The positive fluorescence of 5Ala induced PPIX during surgery proves that demyelinating tissues in tMS are accompanied by mitochondrial dysfunction.

This report captures the reduction in mitochondrial activity in tMS tissue in vivo using the accumulation of 5Ala induced PPIX as an indicator. Decreased mitochondrial metabolic activity may be the underlying cause of tMS formation. Further studies are needed to analyze the pathogenesis.