Recurrent Stroke and Peripheral Neuropathy Associated With Multifactorial Hyperhomocysteinemia: A Case Report

Abstract

Background: Hyperhomocysteinemia is a known risk factor for stroke and neuropathy, though their coexistence is rare. Case Description: A 43-year-old male with chronic myeloid leukemia developed progressive neuropathy and later suffered an ischemic stroke. Investigations revealed severe hyperhomocysteinemia and vitamin B12 deficiency, likely due to chronic nitrous oxide use, folate supplementation without cobalamin, and malnutrition. Despite B12 supplementation, recurrent strokes led to the identification of a homozygous MTHFR 677C>T mutation. Conclusions: This case underscores the essential need to consider all contributing factors and conduct a comprehensive etiological workup, avoiding a narrow focus on obvious causes.

Introduction

We report the case of a 43-year-old male with a history of chronic myeloid leukemia diagnosed in 2016, initially experiencing a 49 Kg weight loss. He was treated with various therapies, including cyclophosphamide, ciclosporin, methotrexate and subsequently dasatinib, followed by an allogeneic stem cell transplant. This was complicated by graft-versus-host disease, leading to cutaneous wounds on the lower limbs, requiring nitrous oxide analgesia every 2 days.

Informed consent was obtained from the patient for this case report. The data has been processed in accordance with the General Data Protection Regulation. No other regulatory procedure in France is applicable to case reports.

Case Description

Since late 2017, the patient developed neuropathy, with progressive lower limb proprioceptive ataxia and neuropathic pain. EMG revealed reduced sensory and motor lower limb nerve amplitudes. Chronic Inflammatory Demyelinating Polyneuropathy was suspected, but no improvement followed intravenous immunoglobulins.

In the spring of 2019, the patient presented with acute right-sided hemiparesis. Brain MRI revealed an ischaemic stroke in the right medulla oblongata (Figure 1A-1B). Spinal cord MRI showed no degeneration or abnormal signals. Initial stroke work-up, including non invasive angiography of cerebral and cervical arteries using magnetic resonance (Figure 1C-1D), electrocardiogram, ECG monitoring using inpatient telemetry for 5 days, transthoracic and transesophageal echocardiography, ruled out atherothrombotic and cardioembolic causes.

Figure 1.

Patient’s MRI Findings for the First and Second Stroke. First Stroke MRI: (A) Axial Cerebral Diffusion-Weighted Imaging (DWI) and (B) Apparent Diffusion Coefficient (ADC) Images Showing an Acute Ischemic Stroke in the Right Medulla Oblongata. (C) Non-invasive Cerebral Angiography and (D) Cervical Artery Imaging, Both Without Abnormalities. Second Stroke MRI: (E) and (F) Axial Cerebral DWI Images Showing Multiple Cortical Infarcts. (G) Non-invasive Cerebral Angiography and (H) Cervical Artery Imaging, Both Without Abnormalities.

Cerebrospinal fluid and blood analyses, including antinuclear (ANA), antineutrophil cytoplasmic (ANCA), beta2-glycoprotein 1 (beta2-GP1), antiphospholipid, intrinsic factor, parietal cell antibodies, lupus anticoagulant, HIV, Lyme and syphilis serology, vitamin B9, and lipid levels were normal. However, serum homocysteine was elevated at 93.8 µmol/L (reference: 5.0-13.9) and cobalamin was decreased at 107 pg/mL (reference: 200-600).

The presumed etiology included, among other factors such as malnutrition, a vitamin B12 deficiency secondary to the medical use of nitrous oxide (Figure 2). Consequently, nitrous oxide was contraindicated, and cobalamin supplementation was initiated. This resulted in stabilization of the neurological symptoms in the lower limbs.

Figure 2.

The Patient’s Clinical Course.

Two years later, despite normalized B12 levels, the patient presented with right-sided hemiparesis. Brain MRI revealed multiple cortical infarcts (Figure 1E-1H), and laboratory tests at admission showed a persistent mild hyperhomocysteinemia at 14.4 µmol/L (reference range: 5.0-13.9). The persistence of hyperhomocysteinemia despite normalized vitamin B12 levels prompted a reassessment of the presumed etiology in this patient. A comprehensive diagnostic workup was repeated, and after ruling out atherothrombotic and cardioembolic causes, investigations focuses on potential underlying causes of the hyperhomocysteinemia. Panel genetic testing revealed a homozygous MTHFR 677C>T mutation, and folinic acid was initiated (Figure 2). Over the next 3 months, despite no further strokes, the patient succumbed to multiple infectious complications.

Discussion

This case highlights the broad range of complications of hyperhomocysteinemia, with both stroke and peripheral neuropathy present in the same patient which is an unusual combination not previously reported in the literature. The patient’s low cobalamin levels were likely multifactorial. First, frequent use of nitrous oxide for wound care likely interferes with vitamin B12 metabolism. ¹ Second, untimely folate supplementation without concurrent cobalamin supplementation may have worsened the deficiency through the “folate trap” mechanism. ² Third, malnutrition related to hematologic disease likely contributed. Recurrent strokes despite vitamin B12 supplementation and persistent hyperhomocysteinemia led to the identification of a homozygous MTHFR mutation.

Homocysteine is a naturally occurring sulfhydryl-containing amino acid that has been implicated in endothelial dysfunction and extracellular matrix proliferation, both of which may contribute to vascular injury. ³

Hyperhomocysteinemia has long been recognized as a thrombosis risk factor due to its procoagulant properties and promoting atherothrombosis through endothelial dysfunction. Hyperhomocysteinemia is a recognized cause of stroke ⁴ and of various peripheral nerve diseases, with axonal neuropathy being the most common. ⁵ While hyperhomocysteinemia is not regarded as a primary contributor to vascular risk when compared to well-established factors such as smoking, hypercholesterolemia, diabetes mellitus, and hypertension, emerging evidence suggests that it may potentiate their deleterious effects through synergistic interactions. This is particularly evident in the context of tobacco use and arterial hypertension. ⁶ Although its pathophysiology is complex and not yet fully understood, hyperhomocysteinemia contributes to vascular injury through multiple pathogenic mechanisms, including oxidative stress, endoplasmic reticulum stress, epigenetic modulation, and protein homocysteinylation.^7,8

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folic acid metabolism. A clear association has been established between plasma homocysteine levels in context of MTHFR C677>T polymorphism and ischemic stroke. ⁹ A recent genome-wide association study conducted in Asian and European populations demonstrated that genetically determined reduced MTHFR activity, associated with hyperhomocysteinemia, is selectively associated with an increased risk of stroke due to cerebral small vessel disease. The analysis of this case is consistent with these findings. ¹⁰

Treatment strategies for hyperhomocysteinemia in the context of cobalamin deficiency due to nitrous oxide consumption include cobalamin supplementation and cessation of nitrous oxide use, although recovery from neuropathy is often slow and may be incomplete. ¹¹

In the context of an MTHFR mutation, standard clinical practice recommends vitamin supplementation combining vitamin B9, vitamin B12, and vitamin B6. ¹² This treatment has been shown to reduce the risk of stroke. ¹³

Clinicians should be alert to both central and peripheral neurological complications associated with the therapeutic or recreational use of nitrous oxide. In the case of an unexplained stroke in a young patient with a negative first-line workup, current practice includes second-line testing for homocysteine levels. ¹⁴ However, in the context of a small vessel stroke in a young patient, homocysteine assessment should be incorporated into the initial systematic workup. ¹⁰

ORCID iD

Alexis Robin https://orcid.org/0009-0009-4330-8148

Ethical Considerations

The data has been processed in accordance with the General Data Protection Regulation. No other regulatory procedure in France is applicable to case reports.

Consent to Participate

Informed consent was obtained from the patient for this case report.

Consent for Publication

Informed consent was obtained from the patient for this case report.