Atypical chronic inflammatory demyelinating polyradiculoneuropathy with ophthalmoplegia and anti-sulfatide IgM positivity

Abstract

Background

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous group of chronic immune-mediated polyradiculoneuropathies. The clinical presentation of CIDP is mainly characterized by a classic peripheral demyelinating sensory-motor type and persists for a minimum of 2 months. However, CIDP may also present with atypical symptoms.

Case presentation: This report presents the case of a patient with CIDP with ophthalmoplegia and anti-sulfatide IgM antibodies. Maintenance intravenous immunoglobulin and glucocorticoid therapies were administered to the patient in accordance with the clinical, laboratory, and electrophysiological findings, which were indicative of CIDP. The treatment partially improved the symptoms, and no recurrence was detected throughout the 3-month monitoring phase.

Conclusions

This study combines a retrospective analysis and a literature review to explore the possible mechanism of CIDP.

Introduction

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a condition that mainly affects the peripheral nervous system and manifests with a wide range of clinical symptoms. Although rare, CIDP can involve the central nervous system. The diagnosis of CIDP relies on clinical manifestations reinforced by cerebrospinal fluid (CSF) analysis and electrophysiological and histopathological findings. ¹ The incidence of cranial nerve involvement in CIDP is low, with a reported rate of approximately 15%. ² Facial and oculomotor nerve disorders are frequently observed,^3–5 while trigeminal and hypoglossal nerve disorders have also been documented.^6,7 However, ophthalmoplegia is only present in 3% to 8% of cases. ⁸ Pathologically, segmental demyelination is caused by antibody-dependent phagocytosis of myelin by macrophages. ⁹ A limited number of reports have suggested the presence of anti-sulfatide IgM antibodies in CIDP patients with ocular palsy, and the underlying pathogenesis is not fully understood. We observed an unconventional case of a patient with CIDP, with the detection of anti-sulfatide IgM antibodies serving as a positive immunological indication. This report provides a retrospective analysis and literature review to explore the possible mechanisms involved in this case of CIDP.

Case presentation

A 56-year-old man with a medical history of hypertension presented with a gradual onset of numbness in his hands and feet that progressed to his upper and lower limbs over 5 months. One week before admission, the patient experienced double vision and was referred to our hospital 12 hours after the onset of weakness in his right lower limb. The patient had received the second dose of the coronavirus disease 2019 (COVID-19) vaccine 6 months prior to admission. There was no history of fever, but the patient reported occasional headaches and vertigo without vomiting. The patient did not exhibit any autonomic or cardiac symptoms, nor did he display any signs of connective tissue disease. There was no familial history of neurological disorders, and no recent substance abuse, alcoholism, or exposure to harmful substances was noted. Upon examination, the patient had limited abduction in both eyes, but no other eye movement impairments or nystagmus were detected in any other directions. The patient had impaired sensation to pinprick and light touch on the right side of the face, but the other cranial nerves were intact. The patient had grade IV muscle strength in the right lower limb. All sensory modalities were impaired in each limb, including light touch, vibration, pinprick, temperature, and proprioception. Both the bilateral finger-to-nose test and heel knee-shin test indicated stable results. The patient had weak bilateral knee tendons, and the bilateral Babinski sign was negative.

A lumbar puncture procedure revealed albuminocytologic dissociation, as evidenced by an elevated protein level of 0.84 g/L and the absence of cells in the CSF, and the glucose level was within normal limits. A comprehensive panel of tests was conducted to measure ganglioside autoimmune antibodies, including IgM and IgG antibody tests for multiple types of gangliosides, such as sulfatide, GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, and Gq1b. The test results revealed a high anti-sulfatide IgM titer in the serum and sulfatide IgM and GM3 IgM positivity in the CSF. However, tests for autoantibodies of the nodes of Ranvier and the COVID-19 polymerase chain reaction test results were negative. Other blood test results were normal, including thyroid function; connective tissue and vasculitis screening; a rheumatic and neoplastic-related examination; and blood glucose, vitamin B12, and folic acid levels. The only positive result was found for anti-nuclear antibodies.

Brain magnetic resonance imaging (MRI) findings were unremarkable and did not show any evidence of cranial nerve hypertrophy (Figure 1). The patient’s electromyography results indicated the presence of axonal demyelinating polyradiculoneuropathy. In addition, a nerve conduction examination demonstrated no existence of sensory conduction velocity and amplitude in the median, ulnar, and tibial nerves on both sides and diminished motor conduction velocity and amplitude in the bilateral median, ulnar, tibial, and peroneal nerves. Moreover, the F wave latency in all examined nerves was prolonged (Table 1).

Figure 1.

Magnetic resonance imaging and magnetic resonance angiography (MRA) of the patient’s brain revealed normal results. (a) Diffusion-weighted imaging (DWI) sequence; (b) fluid-attenuation inversion recovery (FLAIR) sequence and (c) MRA.

Table 1.

Nerve conduction results.

Motor NCS
Nerve	Site		Latency (ms)		Amplitude (mV)		Conduction velocity (m/s)
			Patient	N	Patient	N	Patient	N
Median	Right	Wrist	18.1	<4.1	4.7	>7	n.d.	>50
		Elbow	26.3		4.4		31.7
	Left	Wrist	23.1		2.3		n.d.
		Elbow	27.5		3.6		59.0
Ulnar	Right	Wrist	11.6	<3.2	3.3	>7	n.d.	>50
	Left	Wrist	14.4		6.9		n.d.
Peroneal	Right	Ankle	14.0	<5	3.0	>3.4	n.d.	>40
		Fibula (head)	23.0		2.1		35.5
	Left	Ankle	12.6		2.5		n.d.
		Fibula (head)	21.8		1.7		34.7
Tibial	Right	Ankle	10.8	<5.1	1.4	>4	n.d.	>40
	Left	Ankle	8.8		1.1		n.d.
Sensory NCS
Nerve	Site		Peak latency (ms)		Amplitude (µV)		Conduction velocity (m/s)
			Patient	N	Patient	N	Patient	N
Median	Right		–		–	>12.7	–	>41.8
	Left		–		–		–
Ulnar	Right		–		–	>7	–	>44.2
	Left		–		–		–
Tibial	Right		–		–	>0.4	–	>35.1
	Left		–		–		–
Late responses
			Latency (ms)
			Patient			N
Median	Right		53.6			<30
	Left		59.6
Tibial	Right		75.2			<60
	Left		86.7

NCS: nerve conduction study; n.d.: not determined; –: nonexistent; N: normal values found in our neuroelectrophysiology laboratory.

After obtaining patient informed consent for treatment, the patient was administered intravenous immunoglobulin (IvIg) at a dosage of 0.4 g/kg daily for 5 days, followed by subsequent treatment with glucocorticoids at a dosage of 80 mg/day, which was gradually tapered and stopped. At 3 months after discharge, the patient’s ocular movement disorder had entirely resolved, and neurological examination results were unremarkable. Despite experiencing slight numbness in all limbs, the patient could ambulate slowly without aid. However, the patient refused to undergo additional spinal MRI or electrophysiological examinations. The reporting of this study conforms to the CARE guidelines. ¹⁰

Discussion

CIDP is an autoimmune disorder that progressively affects the peripheral nerves. Despite ongoing research, the root causes of CIDP remain incompletely understood. The disease typically presents with a relapsing or progressive course lasting at least 8 weeks and involves symmetric sensorimotor neuropathy in the proximal and distal segments of all four limbs. The presence of albuminocytological dissociation in the CSF, along with multifocal conduction slowing, conduction block, and temporal dispersion in nerve conduction studies, is required to confirm the diagnosis of CIDP. Furthermore, nerve biopsy may uncover primary segmental demyelination-induced degeneration, frequently accompanied by inflammatory infiltration and onion bulb-like formations. Treatments for CIDP include immune-modulating agents such as corticosteroids, plasma exchange, and IvIg. However, less common variants of CIDP have also been documented.^2,11,12

The patient presented with chronic and symmetrical numbness in both upper and lower extremities, diplopia, asymmetrical limb paralysis, generalized areflexia, and a vaccination history. The electrodiagnostic test results were consistent with the guidelines set by the European Federation of Neurology/Peripheral Nerve Society, which led to a definite diagnosis of CIDP. ¹³ Furthermore, the patient showed albuminocytological dissociation in the CSF, characterized by high protein levels and a normal cell count. The treatment plan involved administration of glucocorticoids and IvIg, ¹⁴ which resulted in positive outcomes. After excluding other potential diagnoses, an atypical form of CIDP was suspected.

Diplopia, also referred to as double vision, is a potential manifestation of CIDP. Single cranial nerve palsies or complex ophthalmoparesis may both result in the occurrence of diplopia. Similar cases have been documented in the literature. For instance, Midori Horiuchi et al. reported patients with CIDP who had ophthalmoplegia and IgM anti-GM1 antibodies, ¹⁵ while Christina Pieh et al. presented a case of CIDP with IgG subset deficiency. ¹⁶ Some cases of CIDP with ophthalmoparesis may be associated with cranial/spinal nerve root hypertrophy.^13,16,17 However, in our case, cranial nerve hypertrophy was not observed. An MRI study revealed that of 14 patients with CIDP, 8 had cervical and brachial plexus hypertrophy. ¹⁸ The duration of the disease course in individuals with hypertrophy was significantly extended, averaging 15.9 years, compared with that in those without hypertrophy, with an average time of only 3.3 years. This result can be attributed to the persistent impact of the ailment.

The presence of anti-sulfatide antibodies is significantly linked to the development of autoimmune-induced acute and chronic polyneuropathy. Sulfatide, an acidic glycolipid, is a unique entity that differs from antiganglioside. It is produced by cells that play a crucial role in the formation of myelin, such as oligodendrocytes in the central nervous system and non-compact myelin Schwann cells in the peripheral nervous system. Within the nodes and paranodes of Langfield, sulfatide assumes a pivotal role in preserving the structural integrity of the nerve sheath membrane, regulates nerve impulses, and facilitates the transmission of membrane information. ¹⁹ Studies have demonstrated that experimental polyneuropathy can be successfully induced in guinea pigs immunized against sulfatide. ²⁰ Additionally, homozygous CST knockout mice that are entirely deficient in sulfatide exhibit progressive neurological deficits from 6 weeks of age and die because of severe abnormal formation of myelinated axons.^21,22 High levels of anti-sulfatide antibodies have been detected in a substantial proportion of patients with Guillain Barré syndrome and CIDP, with percentages of 65% and 87%, respectively. ²³ Campagnolo et al. suggested that sulfatide antibodies can serve as the basis for diagnosing peripheral neuropathy. ²⁴ Furthermore, several studies have found that sulfatide antibodies may be most prominent in axonal sensory neuropathies, similar to the case under consideration. ²⁵

Significant elevations in sulfatide levels have been observed in several brain regions, such as the diencephalon, brainstem, cerebellum, and telencephalon. This increase may result in autoimmune diseases that affect both the central and peripheral nervous systems, owing to a similar underlying pathophysiological mechanism. This phenomenon is known as combined central and peripheral demyelination.^26–28 Peripheral neuropathy may occur concurrently with central nervous system lesions in neuromyelitis optica spectrum disorders and multiple sclerosis cases. ²⁹ Therefore, it is crucial to conduct long-term monitoring of patients to prevent secondary damage to the central nervous system.

Gangliosides consist of acidic sphingolipids that contain one or more sialic acid residues and are unique to peripheral nerves. According to the number of sialic acid residues, gangliosides can be classified as GM, GD, GQ, and GT types, and the type of ganglioside antibody positivity corresponds to different clinical manifestations. ³⁰ However, few reports have described GM3 antibody and CIDP. Recent studies have shown that GM3 antibody positivity is associated with facial palsy and sensory impairment. ³¹ The patient reported here also had sensory disturbance, the mechanism of which is still unknown and requires further exploration.

According to the 2021 European Federation of Neurological Societies/Peripheral Nerve Society CIDP guidelines, the primary pharmacological interventions for CIDP consist of glucocorticoids, IvIg, and plasma exchange. In this case, the patient received IvIg and glucocorticoids, which markedly improved the condition, suggesting that IvIg and glucocorticoids can effectively treat patients with CIDP with anti-sulfatide IgM antibody positivity. However, a thorough examination revealed that future treatment choices could entail complementing inhibitor antibodies and immunological therapies, which appears to be the path of advancement. ¹⁴

Conclusions

One limitation of the study is that a spinal MRI and a second nerve conduction study were not performed after discharge. Despite the absence of any abnormal spinal nerve roots on MRI, a second nerve conduction study could not be carried out because of financial constraints. The purpose of this case study is to highlight the importance of vigilant monitoring and timely diagnosis for healthcare providers. This case may represent a unique subtype of CIDP characterized by cranial nerve involvement and anti-IgM sulfatide antibodies. Identifying unusual presentation patterns and accurately identifying the clinical symptoms is essential to enable prompt and appropriate emergency treatment of CIDP.