The first clinical case of G. spinigerum meningoencephalitis was reported by Daensvang in 1949 (7). Eighteen years later, Chitanondh and Rosen (8) documented the first pathologic evidence of G. spinigerum invasion of the CNS from the autopsy of a 34-year-old Thai woman. In their seminal study, Boongird et al. (9) delineated the clinical syndromes of neurognathostomiasis, which facilitated further prospective and retrospective case identification (10). With the advance of high-resolution neuroimaging, the parasitic tracks of Gnathostoma could be demonstrated on magnetic resonance imaging (MRI), aiding the diagnosis of neurognathostomiasis in the absence of worm recovery (11).

Most (241/248) identified cases of neurognathostomiasis reported in the English-language literature were from Thailand. Two patients were infected in Laos (12,13), 1 in Japan (14), 1 in Myanmar (13), and 2 in South Korea (15,16). One patient had traveled to Southeast Asia and Japan (17), so the geographic origin of his infection could not be determined. The incubation period of neurognathostomiasis can be as long as 10 years because of the long persistence of the nematode larvae in the soft tissues before CNS invasion (2,15), which means it can occur in immigrants in a country in which the parasite is not endemic (16,18). All case-patients were reported to be infected with G. spinigerum. Although gnathostomiasis has been increasingly detected outside of Asia, particularly in Mexico, no cases of neurognathostomiasis have been reported in other regions. The occurrence of another Gnathostoma species in Latin America, namely G. binucleatum, is a possible explanation for this phenomenon.

The first case of neurognathostomiasis in a traveler was reported in 2003 (19). Since then, 4 patients in Europe returning from gnathostomiasis-endemic countries have been published (13,20,21). Two patients traveled to Thailand (19,20), 1 patient to Lao People’s Democratic Republic (13) and 1 patient to Myanmar (13). The patients were reported to have indulged in local customs of eating raw fish (19) and shrimp (20). Gnathostomiasis has been recently reported in travelers returning from southern Africa (22,23). However, the patients had cutaneous manifestation of Gnathostoma spp. infection without neurologic involvement.

Gnathostoma spp. nematodes are highly invasive parasites. After being ingested, the third-stage larvae penetrate the mucosal wall of the gastrointestinal tract. Larvae can enter the CNS by invading directly through the loose connective tissues of the neural foramina of the skull base along the cranial nerves and vessels or through intervertebral foramina along the spinal nerves and vessels (24). The larvae release a variety of molecules into their surrounding environment that facilitate tissue penetration and invasion (25). Proteases are the major molecular types among various components of these so-called excretor–secretory products, both quantitatively and qualitatively (26). In Gnathostoma spp., matrix metalloproteinases might play a key role in invasion of host tissues (27).

Gnathostoma spp. nematodes typically enter the spinal cord along the nerve roots, causing radiculomyelitis (9,28). The parasite is then able to ascend the spinal cord and reach the brain (3,29). This journey may take as long as several years and has been documented in a Thai patient through sequential imaging (29).

Given the length of the migrating larva, which averages 3.0 mm (30), the migration of the worm in the CNS causes direct mechanical injury because of tearing of nerve tissue. The hallmark sign of neurognathostomiasis is the evidence of multiple hemorrhagic tracks; these tracks have been documented throughout the spinal cord and brain tissue by postmortem examination (9), as well as through neuroimaging (31). Subarachnoid hemorrhage can result from larvae burrowing through a cerebral arteriole (32,33). Eosinophilic meningitis caused by Gnathostoma spp. is characterized by erythrocytes in cerebrospinal fluid (CSF) (33), which suggests mechanical damage by the worm. Apart from the structural damage, the inflammatory response to the migrating larvae might further contribute to tissue destruction (34).

The main clinical syndromes of neurognathostomiasis are radiculomyelitis/ radiculomyeloencephalitis, meningitis/meningoencephalitis, and subarachnoid and intracerebral hemorrhage (Table 1). Each syndrome reflects the tissue injury by the migrating parasite. Because the larvae migrate, the same patient can show sequentially different neurologic syndromes. For example, in 1 Laotian patient, meningomyelitis developed, followed by subarachnoid hemorrhage (12). Meningitis, subdural hemorrhage, and then intraparenchymal lesions developed sequentially in 1 patient from northeastern Thailand (29). The most common symptom reported virtually by every patient was pain: radicular pain in cases of spinal involvement (often lasting 1–5 days) or headache in cases of meningoencephalitis. The most common manifestation, spinal cord disease, comprised 55% of all clinical syndromes (Table 1).

Myelopathy in gnathostomiasis is characterized by radicular pain followed by an ascending paresis of lower extremities or quadriparesis with bladder dysfunction (9,10,33,35–38). A sensory level for all modalities including vibration and proprioception was a frequent finding, commonly localized in the thoracic region (9). Cerebral and meningeal involvement is characterized by meningeal signs and decreased consciousness. Abducens nerve palsy was the most common cranial nerve impairment (9,33). Intracranial hemorrhages were seen with sudden-onset focal neurologic deficits such as hemiparesis and hemihypaesthesia (9,10,18,33).

Neuroradiologic Features

Figure 2

Figure 2. Images of the brains of patients with cerebral gnathostomiasis. A) Axial T1-weighted image showing small hemorrhage in the right basal ganglia (arrow). B) Sagittal T2-weighted images showing diffuse cord enlargement with...

Neuroimaging of 11 patients with neurognathostomiasis was reported in English-language literature. On cranial computed tomography, subarachnoid hemorrhage and intracerebral hemorrhage were the most common findings (12,18,33). In 1 patient a subdural hemorrhage was detected (29). The hallmark of cerebral gnathostomiasis on MRI was the detection of hemorrhagic tracks (Figure 2, panels A, C, D). The magnetic resonance signal of a hemorrhagic lesion varies in acute, subacute, and chronic lesions. Hence, on T1 and T2 weighted imaging both hypointensities and hyperintensities have been documented. No gradient-echo T2-weighted sequences have been reported in neurognathostomiasis. However, gradient-echo T2-weighted sequences are exquisitely sensitive to local field inhomogeneities of hematoma and could become a useful sequence in radiologic assessment of cerebral gnathostomiasis.

Diffuse multisegmental spinal cord swelling with corresponding T2 hyperintensities was the most common finding on spinal imaging (11,17) (Figure 2, panel B). Gadolinium enhancement of the lesions was reported in cranial and spinal MRI of 4 patients as slight, nodular, and ill-defined (11,17,35). Table 2 summarizes typical findings on neuroimaging in neurognathostomiasis.

No randomized trials of antihelminthic therapy have been conducted for neurognathostomiasis. We have identified 9 reports of treatment of neurognathostomiasis with albendazole (11,13,17–21,29); 5 patients fully recovered, 2 partially recovered, and 2 patients did not recover. Outcomes might reflect the natural course of the disease rather than the effect of treatment. In several reports, antihelminthic treatment was considered as potentially detrimental and was withheld on the basis of its possible induction of brain edema due to sudden helminthic death (31,38). Three returned travelers from Thailand were treated with albendazole (800 mg/d for 1 month [19], 800 mg/d for 3 weeks [20], and 400 mg 2×/d for 4 weeks [21]) and fully recovered (19–21). In all these patients, dexamethasone (oral or intravenous) or predinsolone was added to the treatment regimen. A recent retrospective evaluation of long-term treatment efficacy in 13 patients from France with imported gnathostomiasis reported 2 patients with neurologic involvement (13), 1 with myelitis, and 1 with encephalitis (C. Strady, pers. comm.). The patient with myelitis fully recovered after albendazole therapy, and the patient with encephalitis was reported to have had 4 relapses despite therapy with ivermectin and albendazole (13; C. Strady, pers. comm.).

Corticosteroids have been used in neurognathostomiasis to treat cerebral and spinal edema (19–21). They also might prevent or alleviate paradoxical worsening after initiation of antihelminthic treatment. However, no conclusion about their efficacy can be drawn from the current data because no randomized control trials have been conducted and the retrospective data are too limited to allow any comparison between the groups. At the moment, no evidence-based recommendations can be issued.

Definitive diagnosis of helminthic CNS infections is notoriously difficult. The recovery rate of worms from the CSF is low, and the invasive procedures for diagnosis are seldom justified (33,35). Neurognathostomiasis is no exception; of 248 published cases, only 27 (11%) were confirmed by recovery of larvae. Moreover, an intermittent subcutaneous swelling, the hallmark of gnathostomiasis, is found only in the minority of neurognathostomiasis cases. Given these difficulties, clinical criteria are useful for practice and research. On the basis of the analysis of published cases, we propose diagnostic criteria that should guide a clinician if a pathologic diagnosis is not possible (Table 3).

Neurognathostomiasis is a parasitic CNS disease endemic to Southeast Asia, particularly Thailand. Because of growing international travel to disease-endemic areas, as well as migration from the tropics, an increasing number of patients will seek medical attention in Europe and North America. Neurognathostomiasis should be suspected in patients who have eosinophilic radiculomyelitis, myeloencephalitis or meningoencephalitis, and a history of travel to gnathostomiasis-endemic areas. Ingestion of raw or inadequately cooked shellfish, freshwater fish, or poultry is a prerequisite for infection; however, because such information might not be volunteered by the patient, clinicians should ask directly about foods eaten during travel. Serologic testing, including Western blot, shows high specificity and can contribute to the diagnosis in an appropriate clinical and epidemiologic setting. No evidence-based protocol is available for treatment of neurognathostomiasis; however, a 3- to 4-week course of albendazole with prednisolone or dexamethasone is 1 of the most frequently used regimens. Clinicians should advise patients traveling to or living in disease-endemic areas to avoid eating undercooked freshwater fish, frogs, poultry, and shellfish.