Malakoplakia is a very rare chronic inflammatory disease that is characterized by the presence of foamy histiocytes with basophilic inclusions called Michaelis-Gutmann (MG) bodies [11]. Generally, this disease affects the urogenital tract but can also affect other organs like the gastrointestinal tract, adrenal glands, skin, lungs, bone and rarely, the central nervous system (CNS) including the cranium and cerebrum [30]. CNS malakoplakia is with only few cases having been reported to date associated with several viral and bacterial pathogens. Although the pathogenetic role of viral or bacterial infection in the malakoplakia has not been confirmed, this disease is generally assumed to be caused by a combination of antecedent chronic bacterial or viral infections in patients with immunocompromised conditions [12]. This process is thought to be the result of dysfunctional lysosomes within macrophages, leading to failure of intracellular killing of ingested organisms or failure to eliminate resulting end products [16]. Effective treatment for this disease has not been identified, leading to a poor prognosis in past cases of CNS malakoplakia.

Spinal cord malakoplakia, a condition not yet reported, is challenging to diagnose, its imaging findings are very similar to those of malignant tumors, making it hard to differentiate between the two. Through this case of spinal cord malakoplakia, we aim to propose a new differential diagnosis for an intramedullary mass in the spinal cord. Furthermore, based on present case, we would like to introduce various management methods for the rare but challenging spinal cord malakoplakia.

This study was approved by the Institutional Review Board (IRB) of Daegu Catholic University (IRB No. CR-24-009), with informed consent waived.

A 61-year-old Korean male was admitted to the emergency room due to worsening symptoms of quadriparesis (limb strength grade 4, left arm weaker than the right) and gait disturbances. The presence of a positive Babinski sign and typical symptoms of cervical myelopathy were observed. A modified Japanese Orthopaedic Association scale 13 points was confirmed.

Seventeen years ago, he was diagnosed with hepatitis C, leading to a liver transplantation 9 years ago. Since then, he has consistently taken mycophenolic acid (750 mg twice daily) as an immunosuppressant. His medical history includes treatment for thymic carcinoma, high blood pressure, diabetes leading to chronic kidney disease, and extended-spectrum beta-lactamases positive Escherichia coli (ESBL-positive E. coli) bacteremia, for which he received long-term antibiotics for complications like acute pyelonephritis (APN) and vertebral osteomyelitis at the T9-10 level.

Initial cervical magnetic resonance image (MRI) showed a 1.2 cm-sized intramedullary enhancing mass at C5 level and two small intramedullary enhancing nodules at cervico-medullary junction and C3-4 level accompanied by diffuse cord edema existed from C1 to T3 level (Fig. 1).

Considering his medical history and radiologic findings, the lesions were thought to be a metastatic tumor in the spinal cord. Surgery with intra-operative monitoring and biopsy was performed. During the procedure, soft, yellowish, and less vascular tissue was revealed after midline myelotomy, indicating infiltration into the pia mater (Fig. 2), complicating dissection. The surgery was halted due to a decrease in the motor evoked potentials (MEP) in the left leg, and further removal was not pursued to prevent potential complications. The immediate post-operative neurological examination showed no difference, but the patient showed mild neurological deterioration on 10 days after surgery. The patient’s left hand grasping power decreased from grade 4 to 2. In the follow-up MRI, an increased size of the non-enhancing lesion was observed (Fig. 3).

The analysis of the specimen revealed many foamy histiocytes with intracytoplasmic inclusions, suggesting the presence of MG bodies. The MG bodies stained positive for von Kossa stain and clusters of foamy histiocytes were CD68 stain positive (Fig. 4). Therefore, the patient was eventually diagnosed with spinal cord malakoplakia.

Oral ciprofloxacin (500 mg twice daily, adjusted for glomerular filtration rate dosage) was initiated, along with simultaneous administration of ascorbic acid and bethanechol. However, due to the overall deterioration of the patient’s condition and the progression of pneumonia, the antibiotic regimen was changed to a broad-spectrum intravenous antibiotics (meropenem and vancomycin) under infectious disease department’s consultation. Due to transplant rejection risks, mycophenolic acid couldn’t be stopped but was reduced from 750 mg to 500 mg twice daily. We continued to use corticosteroids from the beginning to deal with spinal cord edema, but it was not effective. The patient was transferred to the intensive care unit due to respiratory weakness and progressive muscle weakness on 15 days after surgery. The patient became quadriplegia on 17 days after surgery, and subsequently, he expired due to sepsis resulting from aspiration pneumonia.

Malakoplakia, a rare and chronic inflammatory disease affecting multiple organs, was first discovered by Michaelis and Gutmann in 1902 [2], with its histological features described by Von Hansemann in 1903 [21]. The term ‘malakoplakia’ originates from the Greek ‘malakos’ and ‘plakos’ and means ‘soft plaque’ [25]. Most cases of malakoplakia have been limited to one organ; however, multifocal involvement of kidney, bladder and skin has also been reported [20].

The presence of MG bodies in the histiocytes is the pathognomonic and important diagnostic feature of malakoplakia [18]. The exact pathogenesis of this condition is still unknown but would be based on an acquired bactericidal defect in macrophages due to an imbalance between cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), an essential element for phagocytosis [10]. This results in reduced pathogen clearance and macrophage accumulation forming mass-like lesions that mimic cancer.

The pathogenetic role of bacterial infection in malakoplakia has not been confirmed, E. coli is the most frequently related bacteria that has been found in two-thirds of reported cases. Other coliform bacteria like Aerobacter aerogenes and Klebsiella, Enterobacter, Proteus, and Pseudomonas species, have been identified as well [1,33]. Biggar et al. [5] reported that patients with malakoplakia frequently have chronic infections with E. coli. Table 1 indicates that most cases of CNS malakoplakia had an antecedent disease caused by infection [7-9,12,13,15,18,22,23,26,29,31]. According to past literature, CNS malakoplakia is associated with several complex factors beyond just inadequately cleared infections. These factors include the disruption of the blood-brain barrier, which can be caused by meningoencephalitis, infarction, and abscess formation. Additionally, dysfunction of phagocytes due to immunodeficiency or deterioration of the patient’s general condition also contributes to the development of this condition [7,13,26]. Cerebral malakoplakia primarily presented with symptoms like mental changes, seizures, and hemiparesis. In contrast, our case of spinal cord malakoplakia exhibited symptoms similar to typical cervical myelopathy, such as quadriparesis. Both spinal cord malakoplakia and other CNS malakoplakia cases were diagnosed through the identification of MG bodies via biopsy or autopsy. Our case had received long-term antibiotic treatment for APN and vertebral osteomyelitis caused by ESBL-positive E. coli. However, the duration of the antibiotic treatment was insufficient and post-treatment imaging assessments were not performed, making it difficult to ascertain whether the infection had been adequately controlled. These preceding signs of infection are considered important factors in the development of spinal cord malakoplakia, given the possibility of cerebral malakoplakia arising from inadequately cleared infection [12].

Malakoplakia has been reported as a comorbidity in immunocompromised individuals, including organ transplant recipients, malignancy, diabetes mellitus, acquired immunodeficiency syndrome, and malnutrition [28]. Furthermore, disturbances in T lymphocytes or cell-mediated immunity have been implicated in the pathogenesis of malakoplakia as it tends to occur in patients treated with immunosuppressive drugs [6]. Our patient fitted at least three of the above features by suffering from diabetes mellitus, thymic carcinoma and organ transplant recipients.

Based on the previous literature discussing the treatment of malakoplakia, it is recommended to discontinue immunosuppressive drugs, if possible [30]. Graves et al. [14] reported that mycophenolic acid should be limited during the initial treatment due to monocyte suppression. While there were no specific papers discussing the exact timing for discontinuing mycophenolic acid, there were reports indicating that decreased immunosuppression and antimicrobial therapy over several weeks (10-16 weeks) [4,19,27]. The discontinuation and reduction of immunosuppressive agents are still controversial but, it’s crucial to weigh its impact on malakoplakia severity against graft rejection risks.

If feasible, surgical excision combined with appropriate antibiotics has proved beneficial [30]. Previous studies have reported cases of malakoplakia in the vertebrae, showing osteolytic lesions and pathologic fractures on radiologic findings, but treatment was not performed [3,17]. One case of severe low back pain revealed significant stenosis due to bony erosion and an epidural mass. Surgery for debulking and stabilization was successful. Postoperative culture identified E. coli, and appropriate antibiotics were administered. Six months later, the patient was discharged without complications [32]. However, spinal cord malakoplakia posed significant challenges due to adhesions and decreased MEP during surgery, making complete excision extremely difficult. Firstline antibiotics are those with strong intracellular penetration to which the infectious organism is sensitive to, such as sulfonamides, trimethoprim-sulfamethoxazole, and quinolones. Quinolone antibiotic treatment and surgical excision could lead to the highest cure rates [30]. Therefore, we opted for a conservative treatment approach that included oral ciprofloxacin, ascorbic acid, bethanechol and corticosteroids. Despite these treatments, a favorable outcome was not observed. While corticosteroids may help improve renal function in patients with renal malakoplakia, they can also elevate the cAMP level, creating a cGMP/cAMP imbalance that inhibits lysosomal action [10]. Considering the controversy surrounding the use of corticosteroids, it might be considered that prioritizing surgery and the appropriate use of antibiotics could be of greater significance than resorting to corticosteroids.

Considering the rapid worsening of quadriparesis symptoms before admission and after surgery in our case, it can be inferred that spinal cord malakoplakia progresses quite quickly in its clinical course. However, looking at the worsening of neurological deterioration on 10 days after surgery, it is more likely that it was caused by worsened inflammation than simple mass effect. The infection may also lead to apoptosis of neural stem and progenitor cells, thus impairing neurogenesis [24]. This uncontrolled infectious condition may be inferred from the increased size of non-enhancing mass-like lesions on follow-up MRI (Fig. 3). We suggest that persistent immunosuppressive state, worsening of the patient’s general condition, and expansion of the infection due to failure of antibiotic therapy would be responsible for it.

Spinal cord malakoplakia is difficult to differentiate from malignant tumors. The location within the spinal cord poses a risk of nerve damage during operation, making complete excision difficult. Additionally, it tends to progress relatively rapidly, making it extremely challenging to treat. Therefore, without prompt diagnosis and immediate antibiotic treatment, a poor prognosis can be expected. Furthermore, the adjustment of immunosuppressants also requires more active consideration given the risk of spinal cord malakoplakia. As the number of organ transplant surgeries increases, it is anticipated that the number of patients with similar cases will also rise.

To the best of our knowledge, this is the first report of spinal cord malakoplakia. Through this report, we have highlighted the need to be alert to the rapid progression of this disease. As the number of people with immunosuppression is increasing due to organ transplants and other reasons, we should consider the need for careful consideration of this unfamiliar disease, and we look forward to discovering the most appropriate treatment for spinal cord malakoplakia through further clinical research.