Post-infectious Painful Sensory Neuronopathy Following Giardia Infection Responsive to Intravenous Immunoglobulin Treatment

Sensory neuronopathy is a rare pure sensory disorder with characteristic clinical features of early-onset ataxia and a multifocal distribution of non-length-dependent sensory deficits. Diabetes is the most common cause of length-dependent peripheral neuropathy. However, in acute to subacute presentations, conditions such as autoimmune diseases, paraneoplastic syndrome, exposure to toxins, and viral infection could be common etiologies. This report presents a patient with sensory neuronopathy following a Giardia infection. Gait disturbance, neuropathic pain, ataxia, and pseudoathetosis improved by varying degrees following the monthly maintenance of intravenous immunoglobulin (IVIG). An immune-mediated or direct pathogenic attack can explain the underlying pathogenesis behind this patient’s peripheral nerve dysfunction.


Introduction
Sensory neuronopathy, also referred to as dorsal root ganglionopathy or sensory neuron disease, is a rare pure sensory disorder caused by injury to the dorsal root ganglion due to its fenestrated blood supply that permeates blood-borne molecules, antigens, or infecting agents [1]. The hallmarks of this peripheral nervous system dysfunction are early-onset ataxia coupled with multifocal sensory loss proximally and distally [2]. A broad list of etiologies can be grouped into metabolic and paraneoplastic syndromes, autoimmune diseases, drug-related toxins, and infections. Diabetes is the most common cause of length-dependent peripheral neuropathy. However, when confirmed to be of an infectious cause, sensory neuronopathy was traditionally exclusively observed in viral infections. Here, we report an unusual case of sensory neuronopathy following Giardia infection. A complete workup to rule out the common causes of this patient's peripheral nerve dysfunction was unremarkable, leaving Giardia the most likely culprit.

Case Presentation
A 60-year-old female patient was admitted to our service, unable to walk and with unstable gait, ascending sensory deficits, severe neuropathic pain, and pseudoathetosis (proprioceptive deafferentation) four weeks into the diagnosis of Giardia infection. The patient and her daughter confirmed that she had stomach pain, vomiting, and diarrhea. She had a stool test positive for Giardia and received antibiotics at least twice. During her treatment, she started noticing difficulty with her balance and sensory symptoms, rapidly progressing and ascending up to her chest.
On examination, normal motor strength in all muscle groups (5/5 value in Medical Research Council {MRC} scale) was noted. However, the patient exhibited significantly reduced light-touch and pinprick sensations from the torso down in a non-length-dependent pattern, as well as marked loss of vibration and proprioception in all four extremities. She had a normal cranial nerve examination. Deep tendon reflexes were absent in the upper and lower extremities bilaterally.
An extensive neurological workup was unremarkable, including magnetic resonance imaging (MRI) of the brain and cervical, thoracic, and lumbar spine with and without contrast. A computed tomography (CT) of the chest, abdomen, and pelvis revealed no malignancy. A complete metabolic, autoimmune, infectious, neoplastic, and paraneoplastic workup yielded no positive results ( Table 1).   Cerebrospinal fluid (CSF) appeared clear, with a normal protein level, leukocyte count, and IgG index, in addition to negative oligoclonal bands ( Table 1). Electromyography and nerve conduction studies (EMG/NCS) showed a non-length-dependent sensory neuropathy/neuronopathy (  A right sural nerve biopsy revealed acute to subacute axonal neuropathy affecting 40%-50% of axons in all fascicles without regeneration and absent vasculitis or inflammation. A medial gastrocnemius muscle biopsy showed type 2 myofiber atrophy (Appendix).
The patient failed to improve on a five-day course of intravenous (IV) methylprednisolone (1 g) and improved slightly with plasmapheresis. The patient was discharged to an inpatient rehabilitation center and readmitted two weeks after discharge for worsening symptoms. Repeat EMG demonstrated worsening sensory responses in the upper extremities and interval development of mild denervation potentials in some selected muscles. Blink reflexes were also performed, which were normal on both sides (  Due to a significant loss of proprioception in the extremities, the patient lost the ability to fully activate her muscles. Intravenous immunoglobulin (IVIG) (2 g/kg) was administered over five days, and despite making partial improvement initially, the patient later experienced intermittent deterioration. Rituximab (1 g) was then received in two doses two weeks apart, and the patient regained the ability to walk with assistance, but a month later, it was also no longer effective. Response to steroid treatment was likewise poor. It was then decided to continue monthly maintenance of IVIG (1 g/kg). Three months later, the patient regained the ability to walk. Sensory ataxia and pseudoathetosis improved significantly, and neuropathic pain improved partially. The patient continues to be on multiple neuropathic pain medications (duloxetine 90 mg daily, pregabalin 200 mg three times/day, and amitriptyline 100 mg daily). Symptoms failed to improve on IV ketamine and lidocaine infusions.

Discussion
Post-infectious neuropathy is thought to be caused by a direct pathogen invasion into the neuron or an indirect consequence of neurons cross-reacting with antibodies generated during an immune response to infection [3]. For example, Guillain-Barré syndrome (GBS), a common cause of acute post-infectious neuromuscular flaccid paralysis, is an autoimmune disease hypothesized to be induced via molecular mimicry, mainly as a sequela to Campylobacter jejuni enteritis, but has also been seen following other pathogenic infections such as Epstein-Barr virus, cytomegalovirus, and Zika virus [4].
Among plenty of subtypes of peripheral neuropathy is sensory neuronopathy, which is considered a rare entity with limited data on rates of incidence and prevalence available. Nevertheless, it has a distinctive clinical pattern of proprioceptive ataxia combined with non-length-dependent, asymmetrical sensory loss and, occasionally, more severe manifestations of pseudoathetosis and pseudoparesis. In clinical settings, comprehensive investigations are carried out to determine its underlying cause, and even then, around 50% of cases, such as the one we are presenting today, are rendered idiopathic [2].
In our case, we first suspected an underlying systemic neoplasm, refuted with a negative paraneoplastic panel (CSF and serum) and a lip biopsy. Other autoimmune diseases were ruled out with a negative complete immunologic paraneoplastic workup. Moreover, ganglionopathy induced by pyridoxine or chemotherapeutic agents was implausible, given that our patient was not affected by such supplements or drugs [4,1]. Viral infections were similarly eliminated with negative HIV and human T-cell leukemia virus type 1 (HTLV-1) results. Our thorough investigations have thus invalidated all possible causes of this patient's unusual neurological findings, which led us to consider previously unconventional reasons such as Giardia [5].

Conclusions
To date, giardiasis has not been considered among the etiologies of sensory neuronopathy, making this the first report of this rare finding. Giardiasis has not been classically associated with proprioceptive ataxia and asymmetrical sensory deficits, with its manifestations varying from an asymptomatic state to a severe malabsorption syndrome. This case thus adds value to future clinical practice by widening the scope of infectious etiologies of sensory neuronopathies to encompass parasitic infections such as Giardia.
The presented case report illustrates the occurrence of sensory neuropathy following a Giardia infection, extending the common etiologies of sensory neuronopathy to include such parasitic infection. Further research is warranted for this atypical association. Not only will this be instrumental in the rapid recognition of the signs and symptoms indicative of sensory neuronopathy in patients with giardiasis, but also it can pave the way for formulating appropriate management plans on time.

Nerve Biopsy (A and B)
The biopsy shows an active, ongoing axonal neuropathy, with approximately 40%-50% axonal loss in all fascicles. The degree of active axonal degeneration and severity of the loss suggests an acute to subacute process. There is no evidence of significant axonal regeneration. There is no variation in the degree of axonal loss within and among the fascicles. No endoneurial or epineurial inflammation is seen, and there is no vasculitis.
The etiology of the neuropathy cannot be determined from the histologic examination, as is the case in the majority of axonal neuropathies. Both toxic/drug-related axonal neuropathies and acute motor-sensory axonal neuropathy may show similar findings histologically. Please correlate with clinical, laboratory, and electrophysiologic findings.

Muscle Biopsy (C, D, and E)
Type 2 myofiber atrophy is a reactive change frequently associated with disuse, prolonged steroid therapy, aging, and some systemic diseases, among other causes. No chronic neurogenic rearrangement (fiber-type grouping) is seen. The muscle is otherwise unremarkable. There is no evidence of a myopathic process, recent or remote, inflammatory or otherwise. No vasculitis is identified. Please correlate with clinical, laboratory, and electrophysiologic findings.