A Japanese woman in her 60s began to exhibit tremors in her bilateral upper extremities. She had a history of hypertension, cervical spondylosis, and paroxysmal atrial fibrillation. She had no history of alcohol intake, diabetes mellitus, and cancer chemotherapy. At the age of 68 years, the patient began to experience numbness in both upper extremities and gait disturbances. Subsequently, she began to exhibit sensory disturbances, including numbness and dysesthesia in the distal part of her lower extremities and visited the neurology department at the age of 71. The patient showed no fever of unknown origin, and no mucocutaneous manifestations and swollen lymph nodes were found. Neurological examinations revealed muscle weakness and atrophy, dysesthesia, hyperalgesia, marked reduction in vibration and position sense in the upper and lower extremities, and loss of the deep tendon reflex ( Supplementary Table 1 ). The patient showed postural and kinetic tremor in her bilateral hands and diagnosed with essential tremor temporarily, however, drug therapy such as propranolol and clonazepam had no effect. She showed no micturition, defecation, or sexual dysfunction. A nerve conduction study (NCS) revealed marked prolongation of distal latencies (DLs) and very low compound muscle action potential (CMAP) amplitudes in the right median and radial nerves. No CMAPs were evoked in the tibial nerve. Sensory nerve action potentials (SNAP) were not evoked in the right median or sural nerves. Cerebrospinal fluid (CSF) tests revealed markedly elevated protein levels (490 mg/dL, normal range <40). The blood test results, including complete blood count, serum biochemistry, autoantibodies, vitamin levels and tumor markers, were normal ( Supplementary Table 2 ). M protein was not detected in the immunofixation electrophoresis. Abdominal skin punch biopsy detected no evidence of amyloidosis and lymphoma. Sural nerve biopsy revealed prominent edematous changes in the subperineurial space of 5 out 9 nerve fascicules, and edematous changes were relatively mild in the other four nerve fascicles. A reduced number of myelinated fibers and formation of onion bulbs were also visible in the nerve fascicles ( Supplementary Figure 1 ). Genetic tests revealed no pathogenic mutations in hereditary neuropathy-associated genes, including PMP22 ( Supplementary Table 3 ). Finally, the patient was diagnosed with CIDP and received methylprednisolone pulse therapy and high-dose intravenous immunoglobulin (IVIG) therapy. Although her clinical symptoms did not improve, the NCS showed improvement in the DLs, amplitudes of CMAPs, and conduction velocities (CVs) in her median and radial nerves. Two months later, the patient was transferred to the hospital for immunotherapy. She exhibited muscle weakness and atrophy. She also showed dysesthesia, hyperalgesia, marked reduction in vibration and position sense in the distal parts of his upper and lower extremities and extended to both elbows and knees, and a positive Romberg sign ( Supplementary Table 1 ). She exhibited postural and kinetic tremors in her bilateral upper extremities, however, no parkinsonian symptoms including akinesia and rigidity were found. The patient showed no sign of cranial nerve palsy. CSF tests showed a normal cell count (4/mm³) but a marked elevation of in protein levels (625 mg/dL). In the NCS, sensory and motor responses were absent in the median, ulnar, tibial, and sural nerves. Tests for autoantibodies, including anti-ganglioside, anti-MAG (myelin-associated glycoprotein), anti-SGPG (sulfated glucuronyl paragloboside), anti-neurofascin155, and anti-contactin-1 antibodies, were all negative. Lumbar magnetic resonance imaging revealed prominent bilateral hypertrophy of the lumbar roots ( Supplementary Figure 2 ). After admission, three courses of methylprednisolone pulse and seven plasma exchange treatments were administered; consequently, her motor symptoms improved, and CSF protein levels decreased ( Supplementary Table 1 ). Subsequently, oral administration of prednisolone and cyclophosphamide was initiated. At the ages of 72 and 73 years, she was admitted to the hospital and received methylprednisolone pulse, high-dose IVIG, and plasma exchange therapies. Although the CSF protein levels decreased in response to immunotherapy, her motor and sensory symptoms did not improve ( Supplementary Table 1 ). According to the results of sural nerve biopsy at age of 71, the patient could be already at an advanced stage before plasma exchange was started. At the age of 74 years, an initiation of rituximab treatment had been planned for advanced immunomodulatory therapy, however, a few weeks later she was admitted to the hospital as an emergency patient due to disturbance of consciousness and respiratory distress. Although antibiotic therapy was initiated for pneumonia, the patient died of septic shock after a total clinical course of approximately 10 years. An autopsy was performed 20 h and 58 min after death.

The right hemisphere of the brain, some segments of the spinal cord, and right sciatic nerve were frozen for molecular and biochemical studies. The left hemisphere of the brain, rest of the spinal cord including nerve roots, and left sciatic nerve were fixed in 10% buffered formalin. The left sural nerve was fixed in 2.5% glutaraldehyde and embedded in epon, and 1-μm–thick toluidine blue-stained sections were prepared. Ultrathin sections were prepared, stained with uranyl acetate and lead citrate, and examined under a transmission electron microscope (H-7650; Hitachi High-Technologies Co., Tokyo, Japan). The patient’s left biceps brachii and tibialis anterior muscles were collected at autopsy and snap-frozen in acetone pre-cooled on dry ice to minimize cryoartifacts.

After macroscopic observation, appropriate areas were dissected and embedded in paraffin. Paraffin-embedded 6-μm–thick sections of the brain and spinal cord were stained with hematoxylin and eosin (HE) and Klüver-Barrera (KB) staining. Paraffin-embedded sections of the nerve roots, sciatic nerve, and sural nerve were stained with azan. For immunohistochemistry, the primary antibodies used were mouse monoclonal antibodies against CD68 (1:1000, clone PG-M1, Dako, Glostrup, Denmark) and phosphorylated neurofilaments (pNF; SMI31, Covance, Berkeley, CA, USA, 1:10000).

The brain weighed 1200 g before fixation, and macroscopic observation revealed no obvious abnormal findings. By contrast, prominent swelling and hypertrophy of the nerves of the cervical and lumbar plexuses ( Figure 1A ), nerve roots, cauda equina, and peripheral nerves, including the sciatic nerves ( Figure 1B ), were visible. In the spinal cord sections, the outer layers were whitish ( Figure 1C ). In cross-sections of the sciatic nerves, prominent swelling of the nerve fascicles was visible ( Figure 1D ).

KB staining revealed myelin pallor of the peripheral regions of the anterior, lateral, and posterior funiculi of the entire spinal cord, including the cervical, thoracic, lumbar, and sacral cords ( Figures 2A, B ). Peripheral demyelination of the sacral and lumbar cords was most prominent and that of the cervical cord was relatively milder ( Figure 2A ). By contrast, the anterior horn cells and SMI31-positive axons were preserved in severely demyelinating lesions in the spinal cord ( Figures 2B, C ). CD68-positive cells infiltrated the demyelinating lesions but were seen less frequently in the outset layer of the white matter ( Figure 2D ). Swelling of the nerve fascicles was visible in the cervical and lumbar plexuses. ( Figure 2E ), and a large number of onion bulbs were observed at higher magnification ( Figure 2F ). CD68-positive cells markedly infiltrated the nerve plexuses ( Figure 2G ). In both the sciatic and sural nerves, edematous changes were visible in the nerve fascicles, and normally myelinated fibers were completely lost. Numerous onion bulbs were observed in each fascicle ( Figure 2H ). Ultra-microscopic images revealed onion bulbs with more than 20 layers, bands of Bungner, and a marked loss of unmyelinated fibers ( Supplementary Figures 3A, B ). Large fiber-type grouping after denervation was visible in the biceps brachii muscle, and all fibers in the tibialis anterior muscle were extremely atrophic ( Supplementary Figures 4A, B ). Demyelination of the cranial nerves, including the trigeminal, facial, and glossopharyngeal nerves, was also found ( Supplementary Figures 5A–C ), while no demyelinating lesions were visible in the brain upon KB staining.