Vasculitic Tibial Mononeuropathy Associated with Inherited Immune Dysregulation: A Review of Tibial Mononeuropathies with Electrodiagnostic Considerations

Compressive tibial mononeuropathies are uncommon and can be caused by conditions including posterior compartment syndrome, soleal sling syndrome, and tarsal tunnel syndrome. Therefore, it is critical to consider noncompressive etiologies when a tibial mononeuropathy is suspected. This is a patient with a history of rare inherited immune dysregulation that presented to the electrodiagnostic laboratory with severe neuropathic pain in the right foot associated with plantarflexion weakness, concerning for a tibial mononeuropathy. However, the patient’s clinical presentation and results on electrodiagnostic testing were not consistent with any of the above entities. Therefore, noncompressive etiologies of tibial mononeuropathies such as vasculitis had to be considered. The patient subsequently underwent sural nerve biopsy which confirmed small-vessel vasculitis as the cause of the tibial mononeuropathy. She was then started on appropriate immunosuppressive treatment which resulted in significant pain relief and was discharged home. This case highlights the importance of considering noncompressive causes of tibial nerve injury. Compressive and vasculitic tibial mononeuropathies along with their electrodiagnostic considerations are reviewed. Furthermore, this case highlights the critical role of the electromyographer and ability to maximize the impact on patient care through a solid foundation in anatomy, pathophysiology, and electrodiagnosis blended with clinical acumen.

Painless, Symmetric, Ascending Weakness and Sensory Loss

A 60-year-old man sought care for painless, symmetric, ascending weakness and sensory loss affecting the lower, greater than upper, extremities, progressing over 3 weeks with associated orthostatism. He was diffusely areflexic and had symmetric weakness, distal greater than proximal, with normal bulbar strength. Muscle atrophy was not appreciated, and fasciculations were absent. Sensory examination revealed pan-sensory loss at the feet and hands. His gait was unsteady with prominent steppage. He was unable to climb stairs, kneel, or arise without assistance. Pertinent medical and social history included a spinal fusion at C5-T1, a 10-pack-year smoking history, and congestive heart failure, New York Heart Association class III with an intracardiac defibrillator for ventricular fibrillation, and taking carvedilol and furosemide. Needle electromyography and nerve conduction studies showed a severe axonal sensory-motor polyneuropathy with proximal involvement, suggesting polyradicular colocalization. Cerebrospinal fluid obtained during unremarkable spinal myelography, for exclusion of spinal compression, showed normal and abnormal findings: total nucleated cells, 3/µL; glucose, 87 mg/dL; and protein, 326 mg/dL. Sural nerve biopsy showed marked active axonal injury without significant inflammatory infiltrates. Expanded autoimmune neuroimmunologic testing by indirect immunofluorescence staining identified the classic pattern for antineuronal nuclear antibody type 1 –immunoglobulin G. Chest radiography and computed tomography showed a consolidation and volume loss in the left lower lobe without identifiable mass. The patient was diagnosed with paraneoplastic axonal sensory-motor polyneuropathy in the setting of antineuronal nuclear antibody type 1-immunoglobulin G positivity and likely small cell lung carcinoma. Acute motor axonal neuropathy was thought to be the diagnosis, and the patient was treated with plasma exchange. He continued to worsen and was transferred to the intensive care unit with new shortness of breath. Escalated therapy with intravenous immunoglobulin did not help. He had development of urinary retention, bulbar weakness, confusion, and flail limbs in all extremities. On identification of antineuronal nuclear antibody type 1-immunoglobulin G, he was treated with intravenous methylprednisolone, but his condition worsened. The patient and his family opted for comfort measures. His defibrillator was turned off, and he died 20 days after first coming to the hospital. At autopsy, small cell lung carcinoma of the left lung was identified without bronchial mass or metastasis. Neural tissues had diffuse microglial activation, with scattered microglial nodules and prominent perivascular chronic lymphocytic infiltrates. Antineuronal nuclear antibody type 1-immunoglobulin G autoimmunity was first reported in 1965. Patients had sensory neuropathy with nonmetastatic cancer and dorsal ganglia degeneration at autopsy. Neuropathy is the most common neurologic presentation, but the neurologic phenotypes have expanded since the original descriptions to include cerebellar, cognitive, and spinal cord involvement.

Prospective study on usefulness of sural-nerve biopsy

Background: Peripheral neuropathies are a heterogeneous group of disorders, but common among patients attending neurology clinics. A systematic approach, like sural nerve biopsy, is the need of the hour, for a cost effective diagnosis. Studies have shown that nerve biopsy improves treatment in up-to 60% patients. Present study was conducted to evaluate the clinical profile and usefulness of sural nerve biopsy in peripheral neuropathy.Methods: A prospective study was conducted in the Department of Neurology in collaboration with Department of Pathology, Medanta: The Medicity, Gurugram, for a period of six months from January 2019- June 2019. Out of total 82 randomly selected patients, 43 patients were selected for nerve biopsy.Results: Mean age in the biopsy group was 45.61±19.24 years. Duration of illness was less than 1 year in 60.5% patients. In 39.5% of cases, nerve biopsies established the diagnosis and in total 77% of cases it was worthwhile. Hansen’s disease was diagnosed in 44%, CIDP in 12%, Vasculitis in 14%, and diabetes in 7% patients. Biopsy proved more diagnostic when tingling and numbness was there. Diminished DTRs was also statistically significant symptom in biopsy favoring group. Nerve biopsy in multiple mononeuropathy (65.1%) proved more beneficial than in polyneuropathy (32.6%). Similarly, motor-sensory was a predominant presentation in 28 (65.1%) patients with nerve biopsy being more valuable.Conclusions: Nerve biopsy, having a good diagnostic yield, can be a useful aid in cases with multiple mono-neuropathy. It can be the key to prevent long term neurological complications in patients.

Association of Peripheral Neuropathy in Hepatitis C Infection with and without Cryoglobulineamia

Objective: The purpose of this study was to find out the association of peripheral neuropathy in hepatitis C infection with and without cryoglobulineamia. Study Design: Cross sectional study Place and Duration: Conducted in Liver Transplant Unit, Gambat Institute of Medical Sciences, Gambat Khairpur Mirs, Sindh for the duration of six months from November 2020 to April 2021. Methods: Total 50 patients who had hepatitis C infection and peripheral neuropathy were included in this study. Patients were aged between 18- 60 years. Detailed demographics of patients including age, sex and body mass index were recorded after taking informed written consent. When symptoms and evidence of peripheral sensory or motor involvement were evident, clinical neuropathy was diagnosed. Sural nerve biopsy was done on patients and the biopsy specimen was evaluated morphologically and morphometrically. Multiple neuropathy, cranial neuropathy, and polyneuropathy are all terms used to describe peripheral nerve involvement. Our research focused on the motor conduction of the median, ulnar, and common peroneal nerves, measuring MCV, CMAP amplitude, and distal latency (DL) in both patients with and without cryoglobulinaemia for each nerve. The SPSS 20.0 version was used to analyze the data. Results: Mean age of the patients was 46.23±9.87 years with mean BMI 29.16±11.27 kg/m2. There were 30 (60%) females and 20 (40%) were males. We found that 35 (70%) patients had CG involvement with peripheral neuropathy and 15 (30%) cases were without CG. Prevalence of polyneuropathy was higher 19 (54.3%) in CG patients as compared to non CG 2 (13.3%). Mononeuropathy or multiple neuropathy was higher in HCV CG patients 13 (37.1%) as compared to HCV non CG patients 4 (26.7%). 25 patients underwent nerve biopsy (20 CG patients and 5 non CG). Prevalence of epineurial vasculitis and fascicular loss of axons was higher in non CG patients while demyelination + axonal degeneration were prevalent in CG patients. MCV of the deep peroneal nerve in patients with CG+ was low as compared to CG. Even though no statistically significant differences were detected, the other neurophysiological measures pointed to a more extensive and severe involvement of peripheral nerve in CG+ patients. Conclusion: We concluded in this study that the association of peripheral neuropathy in HCV patients with cryoglobulinaemia was greater as compared to non-CG HCV patients. It appears that both CG+ and CG patients suffer from peripheral nerve injury via a vasculitic mechanism, as evidenced by clinical and morphological observations. Serum CG levels indicate a more severe and broad neuropathic involvement, however research suggests that cryoglobulins are not the only element in the vasculitic process. Keywords: Cryoglobulinemia, Peripheral Neuropathy, HCV

Eosinophilic Granulomatosis with Polyangiitis Presenting with Myocarditis as an Initial Symptom: A Case Report and Review of the Literature

A 66-year-old woman with a history of bronchial asthma had shortness of breath and fatigue upon mild exercise. She was diagnosed as congestive heart failure. A blood test showed eosinophilia without the presence of anti-neutrophil cytoplasmic antibody (ANCA), and a myocardial biopsy specimen revealed eosinophilic infiltration in the myocardium. Eosinophilia was improved when she was administered short-term methylprednisolone. After that, she had numbness and pain in her lower limbs with re-elevation of eosinophils. She had dysesthesia and hypalgesia in the distal part of the limbs. Sural nerve biopsy revealed axonal degeneration and thickness of the arterial wall, indicating a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA). Two courses of steroid pulse therapy were performed, resulting in marked improvement of her sensory symptoms. ANCA-negative EGPA might be associated with myocarditis and peripheral neuropathy. A sufficient immunotherapy should have been considered to prevent rapid progression.

Clinical and Neuroimaging Features in Charcot–Marie–Tooth Patients with GNB4 Mutations

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

Nerve Biopsy in Peripheral Neuropathies: Not All Water Is under the Bridge

Sural nerve biopsy has long been a valuable diagnostic tool for the study of peripheral neuropathies, although the recent introduction of non-invasive techniques (e.g., neuroimaging techniques, skin biopsy) and advanced genetic and immunological testing has changed the diagnostic workup of peripheral nervous system diseases. [...]

RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy

Background A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. “Chronic Idiopathic Axonal Polyneuropathy” (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations. Methods We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years. Results The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τb = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio—POR 6.73 CI 95% 2.79–16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τb = − 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03–58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17–22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups. Conclusions This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.