Subacute Combined Degeneration From Isolated Folate Deficiency Secondary to Nutrition and Co-Trimoxazole Use in a Patient With IgG4-Related Disease

Abstract

Subacute combined degeneration (SCD) is characterized by demyelination primarily affecting the dorsal column and lateral corticospinal tracts. It typically presents with paresthesia in the feet and progresses to involve the upper extremities. SCD is commonly associated with nutritional deficiencies, particularly deficiencies of vitamin B12, folate, or copper. Neurological disorders solely caused by isolated folate deficiency are uncommon. Classic presentations of folate deficiency include fatigue, lethargy, glossitis, diarrhea, and the gradual development of megaloblastic anemia. Early SCD diagnosis and treatment, even in the absence of hematological signs, are imperative to prevent irreversible neurological deficits and achieve favorable outcomes. We present a patient with IgG4-related disease who developed subacute sensory ataxia and generalized hyperreflexia. She was eventually diagnosed with SCD, which was attributed to isolated folate deficiency caused by critical illness-related malnutrition and concomitant co-trimoxazole use. Her clinical and neurological examination findings improved at the subsequent 2-week follow-up after effective treatment. Finally, she was able to walk and run independently. This case emphasizes the importance of early recognition of this rare presentation and prompt treatment, which can significantly contribute to better neurological outcomes.

Introduction

Subacute combined degeneration (SCD) of the spinal cord is a rare neurological condition characterized by demyelination, primarily affecting the dorsal columns and lateral corticospinal tracts. Clinically, it typically presents with progressive sensory disturbances, beginning as paresthesia in the lower extremities and advancing to the upper extremities. SCD is most commonly associated with vitamin B12 (cobalamin) deficiency, occurring in approximately 14.8% of patients with vitamin B12 deficiency. ¹ Isolated folate deficiency, although less frequent, can also cause similar neurological deficits. Folate deficiency neuropathy typically presents with a slowly progressive, sensory-dominant pattern, ² and the degree of recovery often depends on the duration of the disease, with shorter disease courses generally associated with better short-term outcomes.^3,4 We describe a case of SCD in a patient with IgG4-related disease, caused by isolated folate deficiency due to malnutrition and prolonged co-trimoxazole use, in the setting of normal vitamin B12 levels and a normal red cell profile.

Case Description

A 60-year-old woman with a known diagnosis of IgG4-related disease (IgG4-RD) presented with a history of progressively unstable gait for one week. She initially experienced numbness in her feet, which ascended to her shins within 4 days, concurrently with difficulty in walking. These symptoms limited her daily activities due to fear of falling. She denied experiencing any weakness.

Prior to this presentation, she was being managed for her IgG4-RD, which initially manifested with marked ascites, profound diarrhea, and significant weight loss. Her baseline serum albumin was notably low (serum albumin was 2.7 g/dL; normal range: 3.4-5.4 g/dL). The definitive diagnosis of IgG4-RD was made based on the current diagnostic criteria, including clinical, serological, and pathological assessments. ⁵ At the time of diagnosis, she had generalized lymphadenopathy, hepatomegaly, ascites, and pleural effusion. A serum IgG4 level exceeded 6410 mg/dL, and histopathology of lymph nodes indicated infiltration of IgG4/IgG cells exceeding 40%. She was initially treated with prednisolone 40 mg daily (1 mg per kg per day) and co-trimoxazole (sulfamethoxazole 400 mg and trimethoprim 80 mg) two tablets twice weekly for Pneumocystis jirovecii prophylaxis. The neurological symptoms described above developed 2 weeks after the initiation of treatment. She had no history of following a vegetarian diet, smoking, alcohol consumption, substance use, or herbal medication use.

On examination, she was not anemic and did not have any skin rashes. Neurological evaluation revealed a decrease in pinprick sensation extending up to the ankles on both feet, loss of proprioception and vibration sensation up to the T10 dermatome level, and generalized hyperreflexia. Motor strength was normal. Romberg’s test was positive, and she exhibited a wide-based gait and decreased step height (Supplemental VDO1).

An initial full blood count exhibited hemoglobin (Hb) of 11.5 g/dL, with mean corpuscular volume (MCV) of 90 fL and red cell distribution width (RDW) of 16.6%. Platelet count was 340,000/μL. The peripheral blood smear demonstrated normochromic normocytic red blood cells and normal morphology across all other cells.

A series of biochemical tests revealed a low serum folate level at 1.4 ng/mL (normal range: 3.1-20.5 ng/mL), normal serum vitamin B12 levels at 594 pg/mL (187-883 pg/mL), an elevated serum homocysteine level at 20.5 μmol/L (normal range: 5-15 µmol/L), and serum methylmalonic acid (MMA) levels at 0.16 nmol/L (normal range: ≤0.4 nmol/mL). Except for a low plasma albumin level, other blood chemistry values were within the normal range.

Additional biochemical tests for other nutritional etiologies of neurological symptoms showed that the vitamin E level was normal at 8.34 mg/L (normal range: 5-20 mg/L). The serum copper level was at the lower end of the normal range, measuring 84 mcg/dL (normal range for females over 60 years: 85-190 mcg/dL). The serum vitamin B1 (thiamine) level was elevated at 125.92 mcg/L (normal range: 28-85 mcg/L).

Magnetic resonance imaging (MRI) of the whole spine with gadolinium contrast did not show any signs of spinal cord compression, nor were there any alterations in intramedullary signal intensity or enhancement. A computed tomography (CT) scan of the brain with contrast was unremarkable. Electrodiagnostic testing indicated mild sensorimotor axonal polyneuropathy.

Our patient’s subacute onset of sensory ataxia and generalized hyperreflexia, with lesions pointing to the dorsal column of the spinal cord rather than peripheral nerves, suggested myelopathy, indicating dorsal cord or posterior spinal cord syndrome. Mild neuropathies from nerve conduction studies did not account for the sensory ataxia. Considering the patient’s history, metabolic causes like subacute combined degeneration emerged as the primary suspects.

We considered nutrient deficiencies, such as vitamin B12 or folate, which are frequently associated with subacute combined degeneration, and copper deficiency, ⁶ which is known to present with dorsal column involvement and may result in similar neurological manifestations. ⁷ Another possible factor, though its typical manifestations can vary greatly, is a vitamin E deficiency. ⁸ These possibilities were evaluated through blood tests. Given the normal MRI results, other possibilities like multiple sclerosis, tabes dorsalis, posterior spinal artery syndrome, or spinal cord compression due to a tumor, hematoma, or abscess ⁶ seemed less likely.

Treatment Approach

The patient was administered a daily regimen of oral vitamin B12 supplement at a dose of 500 mg, in conjunction with folate at a dose of 5 mg per day. Co-trimoxazole was discontinued to prevent further folate deficiency.

Treatment Outcome and Follow-Up

After 2 weeks of folate supplementation, the patient reported a significant improvement in symptoms, including reduced numbness and resolution of ataxia. On subsequent neurological examination, recovery of vibratory sensation was observed. A follow-up 2 weeks later also indicated recovery of proprioception.

Three months post-treatment, blood tests showed a decrease in homocysteine levels to 9.39 mcmol/L, while B12 levels had increased to 1997 pg/mL, and folate levels had normalized to 19.8 ng/mL.

Discussion

SCD is characterized by a pathological demyelination that predominantly affects the white matter, particularly the dorsal column and lateral corticospinal tracts, and less frequently the spinothalamic tract in the spinal cord. Common symptoms begin with paresthesia in the feet and progress to the hands. It may also lead to leg weakness, loss of proprioception, knee or ankle hyperreflexia, sensory loss of lower extremities, ataxia, gait disturbances, and even dementia. ⁶

The patient in this case presented with symptoms that were clinically indicative of SCD. Nutritional causes were investigated through blood tests. Laboratory results revealed normal vitamin B12 and serum MMA levels, but low serum folate and elevated homocysteine, confirming isolated folate deficiency. The key reaction is the synthesis of methionine by the addition of a methyl group from 5-methyltetrahydrofolate (MTHF) to homocysteine, which requires vitamin B12 as a co-factor. In vitamin B12 deficiency, there is a block in folate metabolism and methylation, causing elevated MMA and homocysteine. In folate deficiency, there is a shortage of methylation, causing the elevated homocysteine with normal MMA^9,10 (summarized in Figure 1). The results of the CBC with peripheral blood smear examination, the MRI spine scan, and the CT brain scan were unremarkable despite these findings. The patient’s symptoms represent nonclassical manifestations of SCD, specifically sensory ataxia without weakness, in the absence of abnormal hematologic findings or abnormal MRI results.

Figure 1.

Folate & Vitamin B12 Pathway and Proposed Mechanism of Folate Deficiency

The Summary of the Folate and Homocysteine Metabolism Pathway. ¹¹ In this Patient, We Measured Low Serum Folate and Increased Homocysteine Levels (Depicted With Upward and Downward Red Arrows). Vitamin B12 (Cobalamin), an Essential Co-Factor for Methionine Synthase, is Required for Proper Folate Metabolism and Methylation. Its Deficiency Disrupts Both Pathways. The Proposed Mechanism of Folate Deficiency Involves Impaired Methylation Due to a Reduced Supply of Methyl Groups Required for the Conversion of Homocysteine to Methionine. This Leads to Selective Vulnerability of the Bone Marrow and Nervous System.^12,13. (Abbreviation: MTHFR = Methylenetetrahydrofolate Reductase, THF = Tetrahydrofolate, SAM = S-Adenosyl Methionine, SAH = S-Adenosyl Homocysteine, BHMT = Betaine-Homocysteine S-Methyltransferase, CBS = Cystathionine-β-Synthase, CSE = Cystathionine-γ-lyase, GSH = Glutathione)

In classic folate deficiency, common presentations include fatigue, lethargy, glossitis, and diarrhea. ⁹ Megaloblastic anemia can develop gradually, although neurological manifestations are less common. These could range from peripheral neuropathy to myeloneuropathy,^10,14 restless legs syndrome, ¹⁵ and SCD. ¹⁶ Neuropsychiatric disturbances from folate deficiency, such as depression and cognitive impairment, have also been reported.^10,17 While these neurological disorders are rarely caused by isolated folate deficiency, they are more commonly associated with vitamin B12 deficiency. There have been rare reports of patients presenting with neurological signs alone, in the absence of anemia, in cases of both folate and vitamin B12 deficiency.^10,15,18

Folate deficiency can result from various causes, including inadequate intake, malabsorption, alcoholism, pregnancy, hemolytic anemia, and long-term dialysis.^9,19 Low dietary intake and impaired absorption in the gastrointestinal (GI) tract, due to conditions like celiac disease, gastric bypass, or short bowel syndrome, are common causes. Medications such as methotrexate, phenytoin, sulfasalazine, and trimethoprim ²⁰ can also lead to folate deficiency. In our case, the underlying IgG4-RD and co-trimoxazole-induced condition in our patient presumably led to poor GI absorption with suspected protein-losing enteropathy.

It was hypothesized that the threshold for developing neurological symptoms and anemia due to folate deficiency might be different among patients, even with a shared pathophysiology.^10,15 As in the case of our patient, levels of other essential substances involved in red blood cell production and turnover, such as vitamin B12, remain intact. As a result, neurological symptoms can manifest even in the absence of anemia. The proposed mechanism of folate deficiency causing megaloblastic anemia is the inhibition of the normal proliferation of rapidly dividing bone marrow cells due to impaired nucleic acid synthesis. ²¹ Although the exact mechanism of demyelination in folate deficiency remains unclear, it has been proposed that disruption of the methylation cycle may impair myelin basic protein synthesis, ²² which is essential for proper myelin formation. This contrasts with vitamin B12 deficiency, in which the role in myelin maintenance is well established, primarily due to its involvement in both methylation and the prevention of neurotoxic metabolite accumulation. ⁶ Thus, it may result in more frequently reported diagnoses of SCD from vitamin B12 deficiency than from folate deficiency in the published literature. In SCD, either from vitamin B12 deficiency or folate deficiency, typical MRI findings include symmetrical bilateral T2 hyperintensities in the dorsal columns of the cervical and upper thoracic spinal cord, often described as the “inverted V” or “inverted rabbit ears” sign. In later stages, T2 hyperintensities may also extend to the lateral columns. ²³ However, the normal MRI findings, as in our patient, could be attributed to MRI’s limited sensitivity (14.8-52.8%) ⁴ in detecting pathological lesions in the dorsal column of the spinal cord. ⁶

Regarding treatment responsiveness, this case is consistent with previously published case series describing patients with megaloblastic anemia and neurological manifestations characteristic of SCD who demonstrated clinical improvement following folate supplementation. ¹⁶ A pivotal report published in 1979 by Pincus et al. demonstrated that folate deficiency alone can cause SCD, clinically resembling vitamin B12 deficiency, particularly in the context of malnutrition or antifolate therapy. ²⁴ A similar report has documented patients with clinical and MRI findings typical of SCD, despite normal serum vitamin B12 and MMA levels. ¹¹ These cases highlight the potential for folate deficiency to cause SCD-like neurological manifestations, even though such presentations are considered uncommon.

Folic acid supplementation should be considered as a treatment, but it is crucial to remember that this can mask unrecognized vitamin B12 deficiency and interfere with B12 pathways. Though isolated folate deficiency is relatively rare and can present with diverse clinical symptoms, a high degree of suspicion is essential when patients display neurological dysfunction without hematological manifestations. Delayed diagnosis and treatment in these circumstances can lead to irreversible neurological deficits and unfavorable treatment outcomes. Conversely, as evidenced in our patient, prompt diagnosis and intervention can lead to significantly improved outcomes.

Supplemental Material

Video 1.

ORCID iDs

Manta Yonpiam https://orcid.org/0009-0007-1551-5938

Thanakit Pongpitakmetha https://orcid.org/0000-0002-8338-4649

Wattakorn Laohapiboolrattana https://orcid.org/0009-0004-5333-8758

Jakkrit Amornvit https://orcid.org/0000-0002-9278-2067

Ethical Considerations

The study was reviewed and approved by the local institutional ethical board review, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. (IRB number: 0537/67).

Consent to Participate

Informed consent was obtained from the patient.

Data Availability Statement

The data are not publicly available due to privacy or ethical restrictions. Requests to access the data should be directed to Dr. Thanakit Pongpitakmetha (thanakit.p@chula.md, thanakit.p@chula.ac.th).