Demyelinating polyneuropathy associated with chronic inactive hepatitis B infection

Abstract

This is a case report of a 42-year-old female patient with chronic inactive hepatitis B virus (HBV) infection who presented with relapsing chronic inflammatory demyelinating polyneuropathy (CIDP). Her initial attack was of acute onset (ie, acute CIDP) resembling Guillain-Barré syndrome that responded well to intravenous immunoglobulin (IVIG) therapy. The second episode was chronic and refractory to IVIG. She was managed with plasma exchange, long-term corticosteroids, immunosuppressants and HBV antiviral therapy. She showed both clinical and electromyographic improvement, with no recurrence after 2 years of follow-up.

Background

Hepatitis B virus (HBV) is the leading cause of cirrhosis, hepatocellular carcinoma and liver-related death.¹ Neurological manifestations associated with HBV infection are seldom seen, although they have been reported to occur in 5% of patients infected with HBV. No correlation between HBV genotype and any extrahepatic manifestation of HBV infection has yet been noted.^{2 3} The pathogenesis is not well understood, but most likely it involves an aberrant immunological response to extrahepatic viral proteins or a secondary immune complex (IC) reaction.^{4 5}

In this report, we present a case of relapsing demyelinating peripheral polyneuropathy in a patient with inactive hepatitis B infection with low viraemia.

Case presentation

A 42-year-old woman presented to our Neurology Service with relapsing symmetrical progressive limb weakness, predominantly in the lower limbs, with associated numbness in her hands. She was unable to open water bottles or jars, comb her hair and experienced difficulty going up stairs. She reported no symptoms of sphincter dysfunction and no neck or back pain. She denied any history of fever or upper respiratory infection preceding her illness.

She had another similar attack 16 months ago when she presented with quariparesis associated with areflexia mainly in her lower limbs. She was diagnosed with Guillain-Barré syndrome (GBS) and was administered five doses of intravenous immunoglobulin (IVIG) on 5 consecutive days (0.4 g/kg/dose). Her weakness improved significantly after the IVIG course, and the neurological dysfunction resolved completely over time with physiotherapy. The patient was known to have chronic hepatitis B since childhood, but she was not on any treatment. She had a low viral load (197 IU/mL) on January 2018, with persistently normal alanine transaminase (ALT) levels.

In the current attack, her general examination was unremarkable. She was haemodynamically stable, with normal cardiovascular and respiratory systems. The cranial nerves were intact. The patient had reduced muscle power in (4/5) her upper limbs and (3/5) her lower limbs, with the proximal muscles more affected. Despite reporting subjective numbness, examination of her superficial sensory system revealed no objective abnormalities. Her deep tendon reflexes were absent in both upper and lower limbs. There was no dysautonomia on clinical examination.

Investigations

Nerve conduction studies (NCs) showed diffuse involvement of sensory and motor nerves with conduction blocking in all four limbs, which accords with the European Federation of Neurological Societies criteria of demyelinating polyneuropathy and clinically definite chronic inflammatory demyelinating polyneuropathy (CIDP) (figure 1 and table 1).⁶

Figure 1.

Motor curve showing prolonged onset of distal latency of the left medial nerve compared with the right and significant reduction in the amplitude compound motor action potential. APB, abductor pollicis brevis.

Table 1.

Motor nerve conduction studies prolonged distal latency >50% above the upper limits of normal

MNCS
Nerve	Lat (ms)	Amp (mV)	CV (m/s)	Amp %	Area %	Area (ms*mV)	F-M Lat (ms)
Median motor left
Wrist–APB	11.5	3.5				19.5	–
Elbow–wrist	16.5	2.9	42.0	−17.1	−23.1	15.0
Median motor right
Wrist–APB	8.00	2.8				19.3	–
Elbow–wrist	13.0	2.1	44.0	−25.0	−32.1	13.1

Amp, amplitude; APB, abductor pollicis brevis; CV, conduction velocity; Lat, latency; MNCS, motor nerve conduction studies.

A lumbar puncture was also performed, revealing normal cell counts and high protein levels (80 g/L). MRI of the brain gave a non-specific finding of small white matter lesions. The cervicodorsal spine MRI was normal. Ultrasound of the abdomen revealed coarse liver and normal chest X-ray imaging.

Laboratory results showed elevated ALT of 747 U/L, aspartate transaminase of 286 U/L, alkaline phosphatase of 84 U/L, total bilirubin of 0.42 mg/dL, haemoglobin of 14 g/dL, platelet count of 196×10⁹/L, albumin of 3.6 g/dL, creatinine of 0.41 mg/dL and international normalised ratio of 0.9.

The workup for liver disease revealed positive hepatitis B surface antigen (HBsAg), with negative hepatitis C virus and HIV antibodies. The HBV DNA level was 37 000 121 IU/mL. Autoimmune hepatitis panel, including anti-liver kidney microsomal antibody, antinuclear antibody and anti-double-stranded DNA, was also negative. Transient elastography (Fibroscan) revealed minimal fibrosis (F0-F1).

Treatment

In the current attack, the patient received IVIG (0.4 g/kg/day) for 5 consecutive days, without significant neurological improvement. Instead, her weakness progressively increased over 3 weeks of observation, and so based on her NC finding and the worsening of her clinical condition, a diagnosis of CIDP was considered. She then underwent five sessions of plasma exchange every alternate day and was started on prednisolone 50 mg, azathioprine 50 mg and tenofovir alafenamide 25 mg once a day. The prednisolone dose was gradually reduced over 6 months and was then discontinued. Azathioprine was given in a dose of 50mg and then increased to 100 mg daily. Complete blood count, renal function and liver function were monitored regularly. Tenofovir was administered in a dose of 25 mg once a day for 2 years, that is, until HBV DNA became undetected.

Outcome and follow-up

After maintained therapy with low-dose steroids and immunosuppressant, the patient’s neurological symptoms improved, with no further progression or recurrent attacks, with normal ALT and undetectable HBV DNA at follow-up 2 years later.

Discussion

Chronic HBV infection can cause persistent hepatic inflammation and cirrhosis. However, neurological complications of HBV such as CIDP and GBS have been observed in patients from time to time despite such demyelinating peripheral neuropathies being quite rare. Polyneuropathy develops in approximately 5% of patients with chronic HBV infection and has no correlation with HBV genotyping.^{2 7} It has been demonstrated that these types of neuropathies are IC-related and mediated by cytotoxic T cells. In 1987, Tsukada et al described HBsAg or hepatitis B e-antigen ICs as being significantly increased in both the sera and the cerebrospinal fluid of patients with GBS and CIDP, whereas the serum levels of ICs were also closely related to the clinical status of patients.⁴ These ICs were deposited around the endoneural capillaries and in the endoneurium and were not detected after HBsAg clearance and neurology recovery.^{8 9}

A pathological picture of onion bulb formations, perivascular inflammatory infiltrates and segmental demyelination in affected fibres has been described by Dyck et al.¹⁰ It has also been reported that IC deposition can lead to GBS after HBV vaccination.¹¹ CIDP is the most common chronic immune-mediated inflammatory polyneuropathy, characterised by an insidious onset and becoming progressive over time, affecting proximal and distal muscles symmetrically with impaired sensory function, including loss of reflexes. Up to 16% of patients with CIDP may show acute presentation similar to GBS in what is called acute-onset CIDP (A-CIDP). A-CIDP is less likely to have autonomic nervous system involvement. CIDP can present as a focal or multifocal neuropathy affecting one or both upper limbs.^{12 13} Variants of CIDP have been described, such as multifocal acquired demyelinating sensory and motor neuropathy, multifocal motor neuropathy and distal acquired demyelinating symmetric neuropathy.¹⁴

The first case of demyelinating polyneuropathy with HBV was reported in 1987 by Tsukada et al, and since then, low numbers of patients with good outcomes have been observed. More recently in 2017, Lupescu and Dulamea reported a 57-year-old woman with CIDP who demonstrated clinical and electromyographic improvement with steroid and antiviral therapy.^{4 15} None of the reported cases have correlated the disease exacerbation or severity of demyelinating neuropathy precisely due to the HBV load. Chroni et al reported that demyelinating neuropathies occur in the presence of an exacerbation of chronic hepatitis B with raised liver enzymes and detectable viral load.¹⁶ Reduction in HBsAg expression and ICs by antiviral therapy leads to clinical improvement. Many aetiological factors can cause CIDP: inherited, metabolic, paraneoplastic, toxic neuropathies and nutritional deficiencies, monoclonal gammopathies and autoimmune disease, among others. Infectious diseases such as the HIV, leprosy, borreliosis and diphtheria are also shown as aetiological agents.¹⁷ The other differential diagnosis is vasculitis neuropathy, which classically manifests as mononeuritis multiplex and in this setting, electromyography axonal damage. Vasculitis neuropathy is considered a chronic type of neuropathy and includes chronic relapsing polyneuropathy and chronic relapsing polyradiculoneuropathy (with cranial nerve and respiratory muscle involvement). These types of neuropathy have the characteristic of slow response to steroids.¹⁸

CIDP and GBS can present a similar clinical picture, but the treatment entails individualised treatment strategies, where CIDP, for example, requires plasma exchange, steroid and long-standing immunosuppressive treatment such as azathioprine, mycophenolate mofetil or methotrexate as first-line therapy. Up to 78% of patients with CIDP responded to first-line therapy, and approximately 50% of non-responders benefit from switching between first-line therapy.¹⁹ The administration of IVIG or plasmapheresis may induce anti-inflammatory activity and reduce these ICs or even cause them to disappear. Our patient received IVIG (0.4 g/kg) for 5 consecutive days with clinical improvement in her first presentation, but this benefit could not be replicated during her second presentation. In agreement with our findings, Mori et al reported that patients with CIDP could benefit from IVIG in the initial phase too, but they may fail to respond in the relapse phase and require alternative adjuvant therapy in the form of corticosteroids.²⁰ Our patient had a prolonged inpatient hospitalisation without clinical improvement, but this failure with IVIG was overcome with plasmapheresis, and following this, she has had no recurrence of her symptoms for 2 years after her second presentation.

Learning points.

• Chronic inflammatory demyelinating polyneuropathy is a rare peripheral neuropathy, which can occur in patients with chronically infected hepatitis B (even if inactive) and can present acutely.

• It is a potentially treatable condition that can respond to immunomodulator and antiviral therapy.

• Hepatitis B antiviral therapy may be used as first-line therapy in controlling viraemia and the modifying disease course of the neurological disease.

• Patients with non-responsive or relapsing chronic inflammatory demyelinating polyneuropathy may respond to limited sessions of plasmapheresis.