Effective Management of Chronic Intestinal Pseudo-Obstruction in MELAS Using Acotiamide: A Case Report

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is thought to be the most common subtype of mitochondrial diseases. Recently, upon attention being placed on gastrointestinal symptoms, chronic intestinal pseudo-obstruction (CIPO) has been sometimes observed in patients with MELAS. Patients with CIPO experience vomiting, nausea, anorexia, impaired oral intake, require tube or intravenous feeding, and have a significantly impaired quality of life. Despite the use of various medications, the treatment and management of CIPO are yet to be established. Here, we report a case of effective treatment of CIPO in a patient with MELAS using acotiamide.

A 51-year-old Japanese female presented to our hospital with poor appetite, left temporal headache, and acute paraphasia. Her food intake had decreased during the past several years, and she had eaten one rice ball three or four times a day. She had been having anorexia for 2 years, which worsened 2 days prior to admission.

In her 30s, she developed deafness and diabetes mellitus subsequently. Elevation of the lactic and pyruvic acid levels and calcification in the basal ganglia confirmed the diagnosis of a mitochondrial disorder with m.3243A>G mutation at the age of 38. Since the diagnosis, the patient had not reported any stroke-like episodes.

On physical examination, her height was 153 cm, and weight was 27.8 kg (BMI: 11.9 kg/m²). Neurological evaluation revealed generalized muscle atrophy and aphasia but no apparent limb paralysis. The blood count and coagulation studies were normal; however, the hemoglobin A1c (7.1% [normal range 4.6–6.2%]) and N-terminal pro-brain natriuretic peptide (580 pg/mL [normal range 125 pg/mL]) levels were high. Additional laboratory test results revealed serum lactate (26.4 mg/dL [normal range 4.2–17.0 mg/dL]) and pyruvate (1.34 mg/dL [normal range 0.30–0.94 mg/dL]) elevation, and alginic acid (5.28 nmol/mL [normal range 53.6–133.6 nmol/mL]) decline. Chest radiography, electrocardiography, and echocardiography findings were normal. On the electroencephalogram, high-amplitude slow and sharp waves were observed, mainly in the left occipital region. Cranial computed tomography revealed swelling and decreased density mainly in the cortex of the left temporal lobe. High signal intensity was revealed in the left temporal cortex upon brain magnetic resonance imaging and in the diffusion-weighted imaging and fluid-attenuated inversion recovery sequences (Fig. 1). Magnetic resonance angiography revealed no obstruction of the intracranial vessels.

Considering the stroke-like episode of MELAS and focal epileptic state, we initiated intravenous arginine, edaravone, and levetiracetam. Although the administration of these medications improved the symptoms of aphasia and left-sided headache, the anorexia worsened, and constipation continued throughout her hospitalization.

After 6 days, she presented with nausea and vomiting and abdominal distension. Abdominal contrast-enhanced computed tomography revealed dilatation from the stomach to the intestine, particularly marked in the stomach, with neither obstruction nor impaired blood flow in the intestine (Fig. 2). Gastrointestinal imaging revealed delayed gastric emptying. Upper gastrointestinal endoscopy findings were normal, except for chronic gastritis. Therefore, CIPO exacerbation with MELAS was suspected. Fasting and fluid infusion were initiated; however, the symptoms showed no improvement. Therefore, acotiamide and metoclopramide were initiated. After treatment initiation, the nausea disappeared, and she had her first bowel movement since admission; thus, liquid diet was initiated. Her food intake gradually increased, and she was discharged from the hospital 24 days after admission.

This case report reveals two important clinical issues. First, acotiamide could be considered an effective treatment for CIPO in patients with MELAS. Second, CIPO and stroke-like episodes can be simultaneously observed in patients with MELAS.

Intestinal pseudo-obstruction, which was first reported in 1958, is characterized by obstructive intestinal symptoms, such as anorexia, nausea, vomiting, abdominal pain, constipation, and the absence of actual anatomical intestinal obstruction. CIPO is considered when the intestinal symptoms persist for more than 6 months. MELAS is recognized as a secondary cause of CIPO, and CIPO has been increasingly reported in patients with m.3243A>G mutation [1, 2]. The pathophysiology of CIPO in MELAS is via visceral myopathy owing to the accumulation of intracellular long chain fatty acids, activation of extramitochondrial fatty acid, and generation of excessive reactive oxygen species resulting in secondary CIPO [3]. Previous reports have suggested that large misshapen mitochondria are present in the smooth muscle cells in muscle layers and blood vessels [4]. Moreover, another report demonstrated the possibility of treatment with distigmine bromide for CIPO in MELAS via acetylcholine (ACh) receptors [5]. Acetylcholinesterase inhibitor, acotiamide, can enhance the effect of ACh on the enteric nervous system and could play an important role in the treatment of functional dyspepsia [6]. These findings revealed intestinal dysfunction attributed to energy metabolism defects in the intestinal wall. ACh possibly plays an important role in CIPO; thus, the use of acotiamide could be considered an effective treatment for CIPO in MELAS. Moreover, CIPO management in MELAS is based on conservative treatment. Although a previous case report on coenzyme Q10 treatment for intestinal pseudo-obstruction in MELAS exists, the patient continued to experience intestinal obstruction episodes [7]. Medications that stimulate intestinal motility may help improve the symptoms. For example, erythromycin acts as a motilin receptor agonist and enhances the motility of the stomach and duodenum [8]. Neostigmine, which is a parasympathomimetic agent that acts as an inhibitor of ACh hydrolysis, is effective against CIPO [9]. Although the sample sizes are small, acetylcholinesterase inhibitor pyridostigmine can have beneficial effects for CIPO due to its ability to increase colonic motility [10]. Pyridostigmine is mainly used in the symptomatic treatment of patients with myasthenia gravis and enhances gut motility by increasing ACh availability in the enteric nervous system and neuromuscular junctions [11]. On the other hand, pyridostigmine has some potential side effects such as bradycardia and AV block [10]. Acotiamide enhances the actions of cholinergic neurons localized in the stomach and can exert a prokinetic effect on the gastric antrum, and to improve gastric hypomotility and decreased food intake [12]. From these mechanisms, acotiamide our patient may have improved the symptoms with acotiamide. Metoclopramide are known to exert prokinetic effects via type 2 dopamine receptor antagonism and by increasing ACh release in the enteric nervous system. Metoclopramide is frequently used for intestinal dysmotility, but side effects such as tardive dyskinesia should be noted [13]. Previous reports hypothesized that the energy balance of cells in patients with MELAS remains unchanged. However, a single event (e.g., the first stroke-like episode or acute intestinal pseudo-obstruction) overcomes the threshold and causes the breakdown of the energy system balance and multi-organ deterioration. The hypothesis explaining the co-occurrence of stroke and intestinal pseudo-obstruction is known as the “neurogastrointestinal” crisis [2, 14]. Our patient showed symptoms of stroke-like episodes and CIPO in MELAS. Previous case reports have described multiple clinical manifestations of stroke-like episodes and CIPO [14, 15]. Clinicians should pay attention not only to stroke-like episodes but also to CIPO in patients with MELAS.

Our patient experienced an improvement in the symptoms following acotiamide administration. To the best of our knowledge, this is the first report of acotiamide administration for CIPO. Acotiamide inhibits M1 and M2 muscarinic receptors via antagonistic activity, and partially exerts its prokinetic activity by enhancing ACh release from the stomach [16]. Moreover, acotiamide is thought to exert prokinetic activity by acetylcholinesterase inhibition [17]. In this case report, gastric dilatation was pronounced, suggesting that gastric motility was more pronounced in the intestinal tract. Since our patient did not attend our hospital during 2 years, detailed episode of her symptoms was not clear, but there was a possibility that she had been having gastroparesis for the 2 years. Recent case report shows gastrointestinal complication including gastroparesis and CIPO, of MELAS which led to superior mesenteric artery syndrome [17]. Acotiamide was found to be effective for CIPO management in this case; thus, acotiamide could emerge as a new treatment regimen for not only functional dyspepsia but also gastroparesis [18, 19].

Written informed consent was obtained from the patient for the publication of this case report and accompanying images. Ethical approval was not required for this study in accordance with local guidelines. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000541012).

The authors have no conflicts of interest to declare.

This research was supported by the KAKENHI Grant-in-Aid for Scientific Research (C Number 21K07433).

Conceptualization: Y.K. and A.T.; acquisition of data: Y.K. and T.H.; analysis and interpretation of data: Y.K., Y.N., and K.K.; drafting the manuscript: Y.K.; revising the manuscript critically for important intellectual content: A.T. and A.S.; supervision: A.S.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.