Case Report: Angiostrongylus cantonensis Infection Presenting as Small Fiber Neuropathy

ABSTRACT.

Angiostrongylus cantonensis is an emerging parasite that is the most common cause of eosinophilic meningitis worldwide. Human infection typically presents with headache, neck stiffness, and paresthesia. We report a case of a woman with PCR positive A. cantonensis infection who presented with symptoms of small fiber neuropathy (SFN) but no headache. SFN was confirmed by skin biopsy. After failing standard medications for neuropathy, she was treated with intravenous lidocaine with considerable improvement. However, she required medications for 1 year to treat her chronic neuropathy. Infection by A. cantonensis should be added to the list of causes of SFN, and its potential to cause chronic sequelae should be appreciated.

INTRODUCTION

Angiostrongylus cantonensis is a parasitic nematode that is the most common cause of eosinophilic meningitis in humans worldwide.^1–3 Rats are the definitive host and humans are dead-end hosts who become infected by ingesting intermediate hosts (gastropods) or paratenic hosts (e.g., freshwater crustaceans) that contain infective L3 larvae. A. cantonensis is endemic in Hawai’i, and human infection (also called neuroangiostrongyliasis [NAS]) typically manifests with headache, neck stiffness, paresthesia (tingling, burning, or numbness), muscle aches, and fatigue.^4–6 The spectrum of illness ranges from a mild self-limiting illness to severe disease and even death. Eosinophilic meningitis (defined as 10 or more eosinophils per μL of cerebrospinal fluid [CSF]) is the hallmark of NAS, and the diagnosis can be confirmed by finding larvae in the CSF. However, larvae are rarely found in the CSF so real time polymerase chain reaction (PCR) testing for A. cantonensis DNA in the CSF is used to confirm infection in settings where the test is available.^6,7 (Antibody and antigen detection tests are not standardized and are not commercially available in the United States.)⁷ Treatment of NAS includes corticosteroids, sometimes in conjunction with an anthelmintic such as albendazole.⁶ Long-term sequelae of NAS such as chronic pain and neuropathy are being increasingly recognized.^8–12

Small fiber neuropathy (SFN) is a peripheral nerve disorder involving myelinated A-delta and unmyelinated C nerve fibers. It is characterized by paresthesia, hyperesthesia (painful stimuli are more painful than would normally be expected), and allodynia (normally innocuous stimuli are perceived as painful).¹³ Diabetes and autoimmune diseases are the most commonly identified causes of SFN, while infectious etiologies include HIV, hepatitis C, and Lyme borreliosis.^13–15 The most reliable test for diagnosing SFN is a skin biopsy demonstrating reduced intraepidermal nerve fiber density (IENFD).^16,17 We report a case of a woman with biopsy proven SFN caused by PCR positive A. cantonensis infection. Her extreme allodynia was refractory to standard medications for neuropathic pain but was effectively treated with systemic lidocaine.

CASE REPORT

An adult female resident of Hawai’i presented to the emergency department (ED) with several days of fever, abdominal pain, urinary hesitancy, and generalized pruritus. A complete blood count was notable for leukocytosis (white blood cell [WBC] count 14,000 cells/μL) without eosinophilia. Urinalysis suggested a urinary tract infection and she was treated for acute cystitis and discharged home. The following day she returned to the ED because of worsening abdominal pain, bilateral hip and leg pain, dizziness, diffuse hyperesthesia, and allodynia (worse on her feet and legs.) Urine culture from her initial ED visit grew normal urogenital flora. Her leukocytosis increased and she now had eosinophilia (WBC count 15,500 cells/μL; absolute eosinophil count 574). Laboratory evaluation was otherwise unremarkable. Computed tomography scans of the brain, abdomen, and pelvis were normal. She was hospitalized and her allodynia worsened despite treatment with analgesics. She also developed a sensation of “electric eels swimming through [her] body.” Electromyography and nerve conduction studies were normal. NAS was suspected by the consulting neurologist due to the patient’s constellation of symptoms, residence in an endemic area, and an evaluation which was nondiagnostic up to this point. The patient underwent a lumbar puncture and CSF examination was notable for eosinophilic meningitis with 138 WBCs and 13% eosinophils (absolute eosinophil count 18). Real time PCR of the CSF for A. cantonensis was positive.

The patient was treated with prednisone and albendazole. For her pain she received gabapentin, amitriptyline, duloxetine, and opioid pain medications. By the second week of her hospitalization, she continued to have uncontrolled neuropathic pain and her allodynia was so severe that she could not tolerate any palpation of her lower legs or feet. She was then treated with intravenous lidocaine and approximately 24 hours after the start of the lidocaine infusion, she experienced dramatic improvement of her allodynia. However, intermittent shock-like pains persisted. Skin biopsy obtained from her right leg demonstrated a reduction in IENFD characteristic of SFN (Figure 1). The lidocaine was discontinued after 1 week. She was discharged from the hospital on pregabalin, amitriptyline, oxymorphone, and tramadol. Oxymorphone and tramadol were weaned off after several weeks, but she continued pregabalin and amitriptyline for her neuropathic pain for 1 year.

Figure 1.

Skin biopsies of the patient’s right leg with significantly reduced intraepidermal nerve fiber density. The right calf (A) had 1.7 fibers/mm (normal > 7.1/mm) and the right thigh (B) had 5.5 fibers/mm (normal > 7.0/mm). This figure appears in color at www.ajtmh.org.

DISCUSSION

Viral infections such as HIV and bacterial infections such as Borrelia burgdorferi have historically been associated with SFN, and the protozoan parasite Trypanosoma cruzi has also been linked to SFN.¹⁸ A non-protozoan parasitic etiology of SFN was first reported in 2020 in two patients who acquired NAS by ingesting raw slugs.¹⁹ SFN was diagnosed in these patients by nerve conduction studies utilizing sympathetic skin response testing to evaluate the integrity of postganglionic sudomotor sympathetic fibers, a method that has low sensitivity and unclear specificity compared with the more sensitive and specific skin biopsy.²⁰ Our diagnosis of SFN by the gold standard of skin biopsy in a case of PCR positive NAS validates infection by A. cantonensis as a cause of SFN. The mechanism of nerve injury is not well understood and may be due to neurotoxic effects from the parasite, peripheral eosinophils, inflammatory mediators, or an immune-mediated process.^19,21,22

The significance of identifying A. cantonensis infection as a cause of SFN is 2-fold. First, SFN can be considered a part of the clinical spectrum of NAS. This fact may help reduce delays in the diagnosis and treatment of NAS, although it is not known whether early treatment reduces the risk of developing neuropathy or chronic sequelae. Second, SFN is typically chronic and challenging to treat.^23,24 Thus, recognizing SFN may help clinicians and patients anticipate a prolonged clinical course for which a multidisciplinary approach to management (e.g., neurologists, pain specialists, physical, and occupational therapists) may be beneficial in improving the quality of life and functional status of patients.

Our patient received systemic lidocaine to treat her neuropathy, and this resulted in dramatic improvement of her allodynia. Lidocaine is an amide local anesthetic that is thought to ameliorate pain by suppressing aberrant sodium channel activity within damaged nerve fibers, although the exact mechanism is not known.²⁵ Our patient is the second reported case documenting the effectiveness of lidocaine in treating neuropathic pain attributable to NAS—the drug was also successfully used in a man in Hawai’i with NAS and severe disabling pain.²⁶ In addition, the anesthetic ketamine has been used to treat refractory pain associated with NAS.^11,27 Therefore, adjunctive agents such as lidocaine and ketamine can be considered when treating neuropathic pain associated with A. cantonensis infection.

Our patient received multiple medications for 1 year to treat her chronic neuropathy and she was unable to work during this time. The duration of her treatment and disability highlights the potential for NAS to cause chronic morbidity. Chronic sequelae due to NAS were first reported in the 1980s, and since then there have been multiple case reports from Australia and Hawai’i.^{8–12,28–31} Severe disease with chronic sequelae may be more common in the Pacific basin where infection is usually acquired by ingestion of ground-dwelling gastropods rather than freshwater snails.^10,32,33 This is presumably because terrestrial gastropods such as Lissachatina fulica (the giant African land snail) and Parmarion martensi (the semi slug, an invasive species in Hawai’i) have higher larval burdens than their freshwater counterparts which are commonly implicated as the source of A. cantonensis infections in Asia.^2,34–36

Our patient’s presentation was atypical in that she did not present with headache, a symptom which occurs in 83% of patients with NAS in Hawai’i.³⁷ Clinicians should therefore be aware that the absence of headache does not rule out NAS. Our patient did not have peripheral eosinophilia at her initial ED visit but developed eosinophilia by the time of her hospitalization. Blood eosinophilia is a variable finding in NAS, so its absence also does not rule out A. cantonensis infection.^4,6 The patient regularly consumed raw vegetables but did not have a known ingestion of terrestrial mollusks or freshwater crustaceans, a fact that was unsurprising since a specific exposure is often not identified in NAS cases in Hawai’i.^4,37

In summary, A. cantonensis infection should be regarded as a cause of SFN and clinicians should recognize that NAS can result in prolonged illness and disability due to neuropathy and chronic pain. Intravenous lidocaine may provide some relief in patients with severe neuropathy (especially allodynia) due to NAS.