Out of Sight, Out of Diagnosis—Severe Bilateral Neuropathic Pain in Lower Limbs of a 64-Yr-Old Man

PATIENT INFORMATION

A 64-yr-old man presented with a 1-yr history of severe progressive bilateral pain in the distal lower limbs. He reported no medical history and was not taking any medication, including oral analgesics. In addition, he had no history of alcohol use disorder. He reported no history of groundwater use, proximity to pesticides, or household use of organic solvents. Initial evaluation showed that the pain was localized to the distal lower legs and feet with highest severity in the bilateral soles of the feet and was not isolated to any specific peripheral nerve or root distribution. The pain started 12 mos before his presentation and was described as stabbing, burning, and tingling. His pain became extremely severe few months after onset and was rated as 7 on a numeric rating scale. The pain was exacerbated when his feet contacted objects, the ground, and wind from a fan or air conditioner. The patient had no voiding difficulties. There were no skin lesions on inspection. The dorsalis pedis and the posterior tibial pulses were palpable. Physical examination indicated foot hyperalgesia. In addition, light touch and pinprick sensation in his feet were impaired, although vibration and proprioception remained intact. No sensory deficits were observed in the upper limbs. No motor weakness was observed in the lower or upper limbs, but bilateral knee and ankle reflexes were decreased. There was no ankle clonus, and flexor plantar reflexes were downgoing.

DIAGNOSTIC ASSESSMENT

Nerve conduction study (NCS) and electromyography demonstrated no abnormalities in the peripheral nerves of the lower limbs. Lumbar magnetic resonance imaging (MRI) revealed no abnormalities other than diffuse bulging and an annular tear of the L5–S1 intervertebral disc (Fig. 1). The patient’s pain character and location suggested small-fiber neuropathy. Oral pain medications (meloxicam 15 mg daily, acetaminophen 325 mg/tramadol hydrochloride 37.5 mg twice daily, pregabalin 75 mg twice daily) were administered. However, no pain relief was observed even after 2 mos of medication administration. The patient was lost to follow-up for the next 2 yrs. The patient returned 3 yrs after pain onset still with pain, which had progressed to a numeric rating scale of 8. The pain character and area were the same with that at the initial visit to our clinic. This suggested length-dependent peripheral sensory polyneuropathy. The follow-up NCS/electromyography did not reveal any evidence of axonal damage. Given the patient’s predominantly sensory symptoms with normal NCS, small-fiber neuropathy was the most likely diagnosis.

FIGURE 1: Sagittal (A) and axial (B) T2-weighted MRIs showing diffuse bulging disc at L5–S1. Annular fissure can also be observed as a localized high intensity zone within the annulus (arrows).

Differential Diagnosis

The following diagnoses were considered:

1. Small-fiber neuropathy. The patient’s pain was localized to the distal lower legs and feet in a stocking-and-glove distribution with the highest severity in the bilateral feet. The patient had no motor weakness. Physical examination showed that light touch and pinprick sensations were impaired, but proprioception and vibration perception were not. Given the patient’s clinical symptoms, small-fiber neuropathy was the most likely diagnosis. However, the decreased muscle stretch reflexes and the loss of light touch sensation were suggestive of the involvement of large nerve fibers.
2. Chronic idiopathic axonal polyneuropathy (CIAP). Although electrodiagnostic tests showed no abnormalities, the presence of symmetrical distal sensory symptoms and decreased muscle stretch reflexes supported a CIAP diagnosis. However, because CIAP is a very slowly progressing disorder,¹ the rapid pain progression in our patient suggested the possibility of other disorders.
3. Bilateral S1 radiculopathy. An annular tear on L5–S1 intervertebral disc could have resulted in bilateral S1 radiculopathy. Annular tears are not always visible on MRI.² S1 radiculopathy generally results in posterior calf and foot sole pain. The patient’s pain was the most severe in the soles of the feet. Therefore, the possibility of bilateral S1 radiculopathy was considered.
4. Paraneoplastic syndrome. This condition can be triggered by an altered immune response to a neoplasm, which affects the nervous system.³ Small-fiber neuropathy or sensory neuropathy can be a result of paraneoplastic syndrome, causing distal neuropathic pain in the distal lower limbs.³
5. Vitamin B₆ or B₁₂ deficiencies can cause neuropathic pain. Therefore, tests for vitamin B₆ and B₁₂ levels were performed to rule out deficiencies.
6. Toxic neuropathy. The patient was unemployed and not prescribed additional medications. Given his reclusive lifestyle, it is unlikely that he was exposed to toxic substances that could cause neuropathy. In addition, he reported no history of groundwater use, proximity to pesticides, or household use of organic solvents.
7. Diabetic neuropathy. Because our patient had no history of diabetes with normal A_1c, the possibility of this disorder was minimal.
8. Uremic neuropathy. Considering that our patient had no previous history of renal disorders and renal function tests including serum urea nitrogen and serum creatinine were within normal ranges, the possibility of uremic neuropathy was small.
9. Sjögren syndrome. Peripheral neuropathy is a major neurologic manifestation of Sjögren syndrome.⁴ Sjögren syndrome was not likely because the patient did not have dry eye or dry mouth. The symptoms of sensory neuronopathy caused by Sjögren syndrome are often unilateral and asymmetric, and these predominantly affect the upper limbs. Therefore, we excluded Sjögren syndrome.
10. Chronic inflammatory demyelinating polyneuropathy. Sensory chronic inflammatory demyelinating polyneuropathy may have developed as sensory polyneuropathy. However, because electrodiagnostic test results were normal, chronic inflammatory demyelinating polyneuropathy was ruled out.

Diagnosis and Management

The administration of oral pain medications showed no pain relief. In addition, we performed diagnostic bilateral S1 nerve root block with lidocaine and dexamethasone considering that the cause of pain could be bilateral S1 radiculopathy. However, it did not produce any short- or long-term pain relief. Anti-SSA/Ro, SSA/La, and antinuclear antibody tests were negative. The levels of rheumatoid factor, complete blood count, C-reactive protein, erythrocyte sedimentation rate, vitamin B₆, vitamin B₁₂, serum creatinine, and blood urea nitrogen were within normal ranges. His fasting glucose and hemoglobin A_1c levels were within normal ranges. Thyroid function test results, including thyroid-stimulating hormone and free T4 levels, were also within normal ranges. Antibody to hepatitis C virus and hepatitis B virus surface antigen tests were negative.

Abdominal and chest computed tomography revealed no abnormalities. Whole-body positron emission tomography was performed to search for malignancies. [¹⁸F]Fluorodeoxyglucose uptake in the stomach and in the supraclavicular, axillar, para-aortic, and aortocaval lymph nodes was observed (Fig. 2). A gastroscopic biopsy confirmed gastric mucosa-associated lymphoid tissue lymphoma, whereas a lymph node biopsy of the left supraclavicular lymph node revealed reactive lymphoid hyperplasia.

FIGURE 2: Whole-body positron emission tomography was performed to screen for malignancies. Diffuse [¹⁸F]fluorodeoxyglucose uptake was observed in the stomach (green arrow) and supraclavicular lymph nodes (red arrow).

We believed that the pain may have been associated with paraneoplastic syndrome. Consequently, radiation therapy was administered with 30.6 Gy over 17 fractions for the treatment of mucosa-associated lymphoid tissue lymphoma. After radiation therapy at 40 mos of pain onset, the patient complained of aggravated bilateral pain in the lower limbs (numeric rating scale of 9). Because of tactile allodynia, he had difficulty standing or walking. However, no significant motor weakness was observed in the lower limbs, although the patient showed gait dysfunction as a result of standing and walking imbalance.

CLINICAL COURSE

Follow-up NCS/electromyography showed no abnormalities. We hypothesized that the deteriorated function was a result of general weakness after radiotherapy. The patient was admitted to our hospital for rehabilitative treatment. However, from the first day of rehabilitation, the patient presented with fever that reached a peak of 38.5°C and persisted for 10 days. Blood tests revealed an increased C-reactive protein level (1.634 mg/dl) and erythrocyte sedimentation rate (90 mm/hr). The white blood cell count was within normal limits (4090/μl). Chest radiography, chest and abdominal computed tomography, and urinalysis revealed no abnormalities. Laboratory tests were conducted to investigate the origin of fever. Tests for anti–human immunodeficiency virus (HIV), Epstein-Barr virus, cytomegalovirus, venereal disease, Treponema pallidum hemagglutination, Hantaan virus, leptospirosis, and tsutsugamushi antibodies were included. The HIV RNA level was 192,000 copies per milliliter, whereas the CD4⁺/CD8⁺ antibody level was 0.03. The patient was diagnosed with HIV. In addition to fever, the patient complained of pain during urination. Ultrasound to evaluate prostate pathology revealed an 8.8 × 5.7-mm abscess at the prostate. Brain MRI performed 41 mos after pain onset showed leukoencephalopathy in the white matter of the left frontal lobe.

A combination antiviral agent (Genvoya: cobicistat 150 mg, elvitegravir 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg/d) was administered orally to the patient. One month after treatment initiation (42 mos after pain onset), HIV RNA levels decreased to 101 copies per milliliter. His neuropathic pain reduced from a numeric rating scale score of 8–4. The fever was considered secondary to a prostate abscess. After intravenous administration of vancomycin (1 g) and ciprofloxacin (400 mg) twice daily for 2 wks, the fever resolved. However, a follow-up brain MRI at 2 mos (43 mos after pain onset) showed that leukomalacia had developed in the white matter of the left and right frontal lobes as well as in the bilateral periventricular white matter. This MRI finding was concordant with progressive multifocal leukoencephalopathy, commonly observed in patients with HIV infection.

DISCUSSION

We did not consider HIV-associated peripheral neuropathy because of the low HIV infection prevalence in South Korea (0.02% of the national population, approximately 12,000/50 million people).⁵ Peripheral neuropathies are the most common neurologic complication associated with HIV infection. A review of 37 previous studies reported a variation in prevalence rates from 1.2% to 69% and annual development of neuropathy among HIV-positive patients between 0.7% and 39.7% per year.⁶ A greater risk of neuropathy among older population and patients with more severe disease has been observed.⁶ There are various types of HIV-associated peripheral neuropathies such as distal symmetric polyneuropathy (DSP), inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, mononeuropathy multiplex, autonomic neuropathy, and diffuse infiltrative lymphocytosis syndrome.⁶ Peripheral neuropathy types can be differentiated by disease stage, clinical symptoms, neurologic signs, and diagnostic studies, which include electrophysiology and cerebrospinal fluid analysis.

Severe bilateral pain in the distal lower legs in our patient was likely caused by DSP, the most common neurologic complication associated with HIV infection.⁷ The clinical presentation of DSP is painful feet, with most patients complaining of localized hyperpathia in the feet. Muscle weakness is typically mild or absent. Plasma HIV-1 RNA levels are associated with pain severity.⁸ If HIV infection goes unnoticed, neuropathic pain may become severe. Because clinical findings of HIV-induced DSP resemble those of small-fiber neuropathy caused by other disorders, HIV-induced DSP can be easily misdiagnosed, as in our case. For a definite diagnosis of small-fiber neuropathy, skin biopsy could have been performed in our patient. Chronic idiopathic axonal polyneuropathy is commonly seen in elderly patients, and clinical features are similar to HIV-induced DSP.¹ Therefore, it is not easy to differentiate CIAP from HIV-induced DSP. However, the clinical course of CIAP progresses slowly and often plateaus without any indication of severe pain or disability.⁹ The patient in this clinical report presented with severe pain, which rapidly aggravated during initial months, which is not concordant with CIAP. In our case, the NCS/electromyography tests showed no abnormal findings, which are not common in CIAP. In addition, our patient was misdiagnosed with peripheral neuropathy associated with paraneoplastic syndrome. In our case, the anti-Hu antibody test would have been helpful for differentiating peripheral neuropathy caused by paraneoplastic syndrome.

In most cases of HIV-DSP, small unmyelinated sensory fibers are affected first, followed by large myelinated sensory fibers.¹⁰ Lesions in small unmyelinated sensory fibers are not reflected on NCS. The NCS primarily assesses large myelinated neural fibers and cannot detect lesions in small fibers. This is the reason why electrodiagnostic testing in our patient was normal even though he had severe peripheral sensory polyneuropathy-associated neuropathic pain.

Treatment of HIV-DSP includes the optimization of HIV virologic control. When treating patients with HIV-associated neuropathy in practice, it is important to attempt to maintain sustained virologic control and minimize the use of potentially neurotoxic drugs.¹⁰ In addition, several studies have demonstrated that anticonvulsants, such as gabapentin, lamotrigine, and pregabalin, can effectively manage pain from HIV neuropathy.¹⁰

We incidentally diagnosed the patient while investigating the cause of fever. We suggest that clinicians consider the possibility of HIV-induced DSP in patients presenting with rapidly aggravating neuropathic pain in the feet, with or without distal lower leg involvement. This study conforms to all Resident Fellow Section-CAse REport guidelines and reports the required information accordingly (see Supplementary Checklist, Supplemental Digital Content 1, https://links.lww.com/PHM/B852).