Additional Investigations After the Nerve and Muscle Biopsy Diagnoses

Given the sterile perineuritis revealed by the nerve biopsy and the remote history of cutaneous sarcoidosis, the patient underwent high resolution chest computed tomography (CT). It showed trace bibasilar atelectasis but no lymphadenopathy. CT of abdomen and pelvis was also unremarkable. There was no evidence of systemic sarcoidosis.

Final Diagnosis

Perineuritis with Active Axonal Polyradiculoneuropathy.

Patient Follow-up

After the diagnosis of active perineuritis was made based on the biopsy, the patient received intravenous infusions of methylprednisolone 1 gram daily for 5 consecutive days, followed by oral prednisone 60 mg daily. The patient’s pain markedly reduced. Strength also improved. She was able to ambulate with a walker within a few weeks. Mycophenolate mofetil 1 gram twice daily was added. The patient had a near complete recovery of her motor function within a year. She only had mild residual weakness in the foot and toe dorsiflexors. Immunosuppressant medications were gradually tapered and discontinued after 3 years with close monitoring.

Discussion

Perineuritis is a rare clinicopathological entity. Patients with perineuritis may present with sensory polyneuropathy [1, 2], sensorimotor axonal polyneuropathy [3], chronic polyneuropathy with mixed demyelinating and axonal features [4], or mononeuropathy multiplex [5]. Perineuritis that manifests acute, progressive, sensorimotor, axonal polyneuropathy mimicking Guillian Barre syndrome (GBS) as seen in our case has also been described [6]. Painful paresthesia is a prominent symptom. Perineuritis can be idiopathic but is more often seen in association with a systemic disease such as sarcoidosis, leprosy, cryoglobulinemia, ulcerative colitis, intoxication with adulterated rapeseed oil, or systemic malignancy [5–8]. Our case appears to represent idiopathic perineuritis. Although the patient had a remote history of cutaneous sarcoidosis and breast cancer, there was no evidence of systemic sarcoidosis or malignancies at the time of neuropathy evaluation. The combined sural nerve and gastrocnemius muscle biopsy did not show granulomas or micro-organisms. The link between the perineuritis and prior cutaneous sarcoidosis is uncertain.

The differential diagnosis of an acute, painful, rapidly progressive, polyneuropathy includes GBS, vasculitic neuropathy, other inflammatory neuropathies such as sarcoid granulomatous neuritis and perineuritis, infectious neuropathies, and toxic neuropathies. GBS mimics should be considered when the disease course is atypical and the treatment response is poor. Our patient presented with acute worsening of paresthesia and rapid progression of limb weakness with reduced peroneal and tibial CMAP amplitudes and normal sensory NCS, which made the initial consideration of GBS reasonable. However, the onset of mild sensory symptoms 2 months prior to the acute worsening, and the lack of any improvement over the course of 3 months despite the repeated courses of IVIg treatment made the GBS diagnosis questionable. It raised a strong suspicion for an active inflammatory myopathy other than GBS such as vasculitic neuropathy. Given the past medical history of breast cancer and sarcoidosis, paraneoplastic neuropathy and sarcoid neuritis were also of concern. The patient did not have signs of infection or a history of neurotoxin exposure . A nerve biopsy was needed in this clinical setting to address the GBS mimics.

The sural nerve biopsy in our patient showed striking active perineuritis. Perineuritis is a rare but distinct pathological diagnosis. The nerve pathology of perineuritis is characterized by prominent perineural inflammation, damage, and thickening along with axonal degeneration as seen in our case [6]. Endoneurial and epineurial perivascular inflammation is commonly seen. The inflammation and thickening of perineurium are often focal or irregular with fascicle-to-fascicle variations. Electron microscopy (EM) typically reveals foamy histiocytes and lymphocytes infiltrating and splitting perineurial lamellae, perineurial cell necrosis, and thickening of perineurium with excessive collagen deposition [3, 5, 6]. When associated with sarcoidosis, granulomas may be present in the endoneurium or epineurium (see Fig. 2.​6 in Chap. 2) [6]. When associated with leprosy neuritis , additional features such as granulomas, acid fast bacilli, more severe epineurial and endoneurial inflammation, and neural architectural damage are often present [9] (see the chapter of “Leprous Neuropathy”). The nerve biopsy finding of perineuritis should prompt a careful search for sarcoidosis and leprosy. In our case, although the patient had a remote history of cutaneous sarcoidosis, the high resolution chest CT and the abdomen and pelvis CT did not reveal any evidence of systemic sarcoidosis. The nerve biopsy did not show granulomas. The nerve inflammation was relatively confined to perineurium, and the FITE stain did not show acid fast bacilli to suggest leprosy neuritis.

A sural nerve biopsy can differentiate GBS from other inflammatory neuropathies which can clinically mimic GBS. A nerve biopsy in GBS typically shows prominent endoneurial inflammation rather than perineurial inflammation, along with active demyelination and/or axonal degeneration. A nerve biopsy in acute vasculitic neuropathy often shows acute vasculitis changes and axonal degeneration with interfascicular and/or intrafascicular variations (see Figs. 2.​2, 2.​3, and 2.​13 in Chap. 2 and the chapter of “Vaculitic Neuropathy”).

As perineuritis is rare, the natural history and the treatment response to immunosuppressive or immune modulating therapies have not been studied. According to the limited number of case reports, steroids appears effective.

Pearls