HTLV-1-associated demyelinating neuropathy: A case report and review of the literature

Abstract

A 78-year-old man developed paresthesias in the extremities. He was referred to our hospital because of positive anti-human T-cell leukemia virus type 1 (HTLV-1) antibodies in the serum and the presence of abnormal lymphocytes. He was diagnosed as chronic-type adult T-cell leukemia/lymphoma. Neurological examination revealed sensory impairment in the distal parts of the extremities with loss of deep tendon reflexes. Nerve conduction study showed motor and sensory demyelinating polyneuropathy, indicating a diagnosis of HTLV-1-associated demyelinating neuropathy. Corticosteroid therapy followed by intravenous immunoglobulin therapy improved his symptoms. Since demyelinating neuropathy associated with HTLV-1 infection is not well recognized, we here report its characteristics and clinical course through our case report and literature review.

Highlights

• •We report a 78-year-old man, who was infected with HTLV-1, developed unsteadiness in his gait associated with sensory ataxia.
• •Nerve conduction study showed motor and sensory demyelinating polyneuropathy.
• •Corticosteroid and IVIg therapy improved his symptoms.

1. Introduction

The prevalence of human T-cell leukemia virus type 1 (HTLV-1) infection is estimated to be at least 5–10 million people worldwide. The prevalence in Japan is estimated to be at least 1.08 million people according to a 2006 to 2007 survey [1]. Although the majority of HTLV-1-infected individuals remain asymptomatic for life, approximately 3%–5% of HTLV-1-infected individuals develop adult T-cell leukemia/lymphoma (ATL) [2] and 0.25%–3.8% develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [3]. HTLV-1-related peripheral neuropathy is commonly associated with HAM/TSP [4]; however, one study estimated the frequency of HTLV-1-related peripheral neuropathy without HAM/TSP as 6.3% among HTLV-1 infected individuals [5].

Although these HTLV-1-associated peripheral neuropathy manifest mostly as a predominantly sensory axonal polyneuropathy, there is also demyelinating polyneuropathy [5].

Here, we report a case of demyelinating polyneuropathy similar to chronic inflammatory demyelinating polyneuropathy (CIDP) without concomitant HAM/TSP, in relation to the literature.

2. Case presentation

A 78-year-old man presented with paresthesias in his left lower extremity, which spread to the four extremities a few weeks later. After 3 months, his gait became unsteady. He was referred to our hospital due to the presence of anti-HTLV-1 antibodies and abnormal lymphocytes in blood tests. He was from Nagasaki in the Kyushu area of Japan and his sister died of ATL. He had no history of blood transfusion or organ transplantation. Blood tests in our hospital revealed 8700/μL white blood cells (lymphocytes; 4724/μL with abnormal lymphocytes of 0.5% by visual inspection) and normal levels of lactate dehydrogenase and calcium. Chest and abdominal computed tomography showed no significant lymphadenopathy but showed hepatosplenomegaly, and he was diagnosed with chronic type ATL according to the Shimoyama criteria subtype classification [6]. The blood test one month later showed no increase of abnormal lymphocytes with normal soluble interleukin-2 receptor levels, therefore, the activity of ATL was considered to be stable, and follow-up without treatment was selected. The patient was admitted to our department for neurological assessment. There were no abnormal findings in cranial nerves. He had no muscle atrophy, and muscle strength according to manual muscle testing was 5/5 in the extremities and the trunk. The deep tendon reflexes of the extremities were absent, and we observed sensory impairment of all modalities in the distal parts of the extremities. Temperature and pain sensation and deep sensation were severely impaired. There were no pathological reflexes including Babinski signs. Romberg's sign was positive. He had unsteadiness in his gait which resulted from sensory ataxia and he required a cane when walking.

Cerebrospinal fluid (CSF) examination showed a cell count of 3/μL, protein level of 181 mg/dL, IgG of 16.2 mg/dL, and anti-HTLV-1 antibody titer (using the particle agglutination method) was 512-fold. The CSF biomarker levels for HAM/TSP were moderately higher than normal: neopterin 7 pmol/mL and C-X-C motif chemokine 10 (CXCL10) 904.1 pg/mL [7]. However, this case did not show myelopathic features (spastic paraparesis, bladder rectal disorder), and cervical to thoracic magnetic resonance imaging (MRI) showed no spinal stenosis or CSF blockage.

A nerve conduction study (Table 1) showed demyelinating polyneuropathy in motor and sensory nerves. Conduction block was observed in the right ulnar nerve and temporal dispersion was observed in the right tibial nerve.

Table 1.

Results of the nerve conduction study.

	DL, ms (UL)	CMAP, mV (LL)	F wave latency, ms (UL)	MCV, m/s (LL)	SNAP
Rt. median neve	5 (4.2)	6.1 / 5.0 (3.5)	34.4 (31)	38.7 (48)	N.E.
Rt. ulnar nerve *	3.9 (3.4)	4.0 / 2.1 / 1.4 (2.7)	25.2 (32)	31.0 (49) /24.4 (50)	N.E.
Rt. tibial nerve ⁑	6.6 (6.0)	1.8 (2.9) / 0.74 (2.5)	33.5 (58)	23.9 (41)	–
Rt. peroneal nerve	12.3 (5.5)	0.35 / 0.24 / 0.44 (2.5)	N.E.	29.0 / 15.0 (40)	–
Rt. sural nerve	–	–	–	–	N.E.
Lt. median neve	8.7 (4.2)	1.4 / 1.8 (3.5)	42.4 (31)	30.5 (48)	N.E.
Lt. ulnar nerve	5.9 (3.4)	1.9 / 1.0 / 1.3 (2.7)	–	29.7 (49) / 33.3 (50)	N.E.

Reference values are indicated in () after the measured values

*Conduction block was observed in the right ulnar nerve. ⁑Temporal dispersion was observed in the right tibial nerve.

Abbreviations: UL, Upper limit; LL, lower limit; DL, distal latency; CMAP, compound motor action potential; MCV, motor nerve conduction velocity;

SNAP, sensory nerve action potential; N.E., not evoked; Rt., right; Lt., left.

F wave latency of left ulnar nerve and other nerves of the left side were not examined due to patient pain.

Blood tests excluded autoimmune disorders, including Sjogren's syndrome and rheumatoid arthritis, and nutritional/metabolic disorders as a cause of neuropathy. Anti-myelin-associated glycoprotein, anti-neurofascin 155, and anti-contactin-1 antibodies were negative. Based on the high anti-HTLV-1 antibody titer in the serum and CSF, we made a diagnosis of HTLV-1-associated demyelinating neuropathy.

We administered methylprednisolone (mPSL) pulse therapy (1000 mg/day for 3 days) for a total of two cycles but there was little improvement in neurological symptoms; thus, we added intravenous immunoglobulin (IVIg) therapy (400 mg/kg/day for 5 days) from the 6th day after mPSL pulse therapy. Paresthesia in the extremities improved immediately on the second day of the initiation of IVIg. CSF biomarker after the mPSL pulse therapy was reduced with neopterin of 6 pmol/mL and CXCL10 of 624.1 pg/mL. The patient was observed without treatment, and 5 months later, the paresthesia of the extremities reoccurred. After adding 2 cycles of mPSL pulse therapy, the paresthesia improved. We then placed the patient on maintenance oral prednisolone, and after 6 months no recurrence has been reported.

3. Discussion

The present case demonstrated chronic paresthesia in the distal part of the extremities without spastic paraparesis or bladder rectal disorder. A nerve conduction study revealed demyelinating neuropathy. Table 2 shows previous reports of HTLV-1-associated demyelinating neuropathy in comparison to the current case. These cases were diagnosed by nerve conduction study or sural nerve biopsy. Our patient responded well to IVIg, but most previous reports to date utilized steroid therapy. The immediate improvement of our case after IVIg may have been due to the effect of the mPSL pulse therapy. Regarding IVIg therapy, there is a case report that IVIg therapy was ineffective for HTLV-1-associated demyelinating neuropathy [8] and IVIg therapy may not be considered as the first choice. The selection of appropriate treatment should be the focus of future research.

Table 2.

Previous case reports of HTLV-1-associated demyelinating neuropathy.

Age/Sex	Neurological complaints	Diagnostic basis	ATL	HAM/TSP	Other complications	Treatment	Authors /year
53/F	Muscle weakness	NCS / biopsy	−	−	−	Prednisolone	Arakawa et al./ 1990
65/F	Not listed	NCS / biopsy	−	+	−	Not listed	Kiwaki et al./ 2003
50/M	Not listed	NCS / biopsy	−	+	GBS	Not listed	Kiwaki et al./ 2003
70/F	Not listed	NCS / biopsy	−	+	SjS	Not listed	Kiwaki et al./2003
80/F	Not listed	NCS / biopsy	−	+	−	Not listed	Kiwaki et al./ 2003
41/M	Paresthesias	NCS only	−	−	−	Not listed	Leite et al./ 2004
46/F	Paresthesias	NCS / biopsy	−	−	−	Not listed	Leite et al./ 2004
21/M	Not listed	NCS only	−	−	−	Not listed	Leite et al./ 2004
69/F	Pain, muscle weakness	NCS / biopsy	+	−	−	mPSL pulse	Matsui et al./2006
58/M	Muscle weakness, paresthesias	NCS / biopsy	−	−	DM	mPSL pulse IVIg	Yamamoto et al./ 2018
78/M	Paresthesias	NCS only	+	−	−	mPSL pulse IVIg	Present case

Abbreviations: DM, diabetes mellitus; F, female; GBS, Guillain– Barre syndrome; IVIg, intravenous immunoglobulin; M, male; mPSL, methylprednisolone; NCS, nerve conduction study; SjS, Sjogren syndrome.

CSF biomarkers of HAM/TSP usually assess central inflammatory activity. Although our patient did not show myelopathic features, we observed elevations of neopterin and CXCL10, which are CSF biomarkers for HAM/TSP. It is unclear whether central inflammation activity observed in our case might affect the demyelinating neuropathy. Alternatively, it may reflect latent central inflammation that has not yet manifested as symptoms in the patient. Therefore, it is necessary to carefully observe this patient for the future development of HAM/TSP, that is; appearance of spastic paraparesis or bladder rectal disorder. When HAM/TSP is suspected, cervical to thoracic MRI and CSF biomarkers should be performed.

Pathophysiological differences between HTLV-1-associated demyelinating neuropathy and CIDP have not been clarified in previous studies. Phagocytosis of myelin by macrophages is thought to induce demyelination in CIDP patients [9]. From the few reports so far regarding the findings of sural nerve pathology in HTLV-1-associated demyelinating neuropathy, there are reports of mixed demyelinating degeneration and axonal degeneration [8] and association with macrophage infiltration [10]. Here it is speculated that HTLV-1-associated demyelinating neuropathy may be mediated by the same immune-mediated mechanisms seen in myelopathy in HAM/TSP, but further investigation is warranted [4].

In the southern part of Japan, especially in Kyushu and Okinawa regions, the presence of HTLV-1 carriers has been reported. Clinicians responding to demyelinating neuropathy should consider screening patients who have a history of the above birthplace, blood transfusion, or organ transplantation.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

K.T., T. M., Y. Tateishi, and Y. Tsuboi contributed to the conception and design of the research. K. T. wrote the first draft of the manuscript. H. M., H.O., J.T., S.F., and Y. Tsuboi revised the manuscript. All the authors have read and approved the final version.

Compliance with ethics guidelines

The present report was approved by the Ethics Committee of Fukuoka University. The patient gave informed consent.

Declaration of Competing Interest

The authors declare no conflict of interest for this article.