Proteinuria is a key to suspect autoimmune nodopathies.

BACKGROUND AND PURPOSE: Reports of patients who have autoimmune nodopathies concurrent with nephrotic syndrome are increasing. We investigated whether proteinuria could be a biomarker of autoimmune nodopathies. METHODS: Qualitative urinalysis results were retrospectively obtained from 69 patients who were diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) at a hospital in Japan. Proteinuria was graded as mild to severe (i.e., mild, 30-99; moderate, 100-299; severe, 300 mg/dL or more) according to the results of the urine dipstick test. Autoantibodies against the paranodal proteins contactin 1 (CNTN1), neurofascin 155 (NF155), and contactin-associated protein 1 (Caspr1) and the nodal protein neurofascin 186 (NF186) were measured, and the predominant IgG subclass was determined by enzyme-linked immunosorbent assay in sera from the 69 patients. RESULTS: Four patients (6%), five patients (7%), and one (1%) patient were positive for anti-CNTN1, anti-NF155, and anti-Caspr1 IgG4 antibodies, respectively. No patients had IgG4 antibodies against NF186. Proteinuria of mild or greater levels was found in three patients with anti-CNTN1 IgG4 and two patients with anti-NF155 IgG4 antibodies. The autoantibody-positive patients more frequently had proteinuria of mild or greater levels than the seronegative patients (p = 0.01). CONCLUSIONS: Proteinuria is a possible biomarker of autoimmune nodopathies associated with autoantibodies targeting CNTN1 or NF155. Urinalysis results should be carefully checked for quick differentiation of autoimmune nodopathies from CIDP. Patients who present with nephrotic syndrome should be tested for anti-CNTN1 IgG4 antibodies, and patients who exhibit mild proteinuria should be tested for anti-NF155 IgG4 antibodies.

IgG subclass shifts occurring at acute exacerbations in autoimmune nodopathies.

BACKGROUND: Autoimmune nodopathy associated with anti-contactin1 (CNTN1) IgG4 antibodies frequently manifests as acute axonal degeneration in addition to detachment of the paranodal myelin loops. The acute destruction of myelinated nerve fibers does not match the function of IgG4, which cannot activate the complement pathway. IgG subclass switching from IgG1 or IgG3 to IgG4 has been observed in some patients with autoimmune diseases associated with IgG4 throughout their disease course. METHODS: Serial changes in IgG subclasses, clinico-neurophysiological features, and nerve and renal pathology were reviewed in three patients with anti-CNTN1-associated autoimmune nodopathy and one patient with anti-contactin-associated protein1 (Caspr1) autoimmune nodopathy. RESULTS: All four patients had predominantly IgG4 autoantibodies, whereas they showed evidence of acute axonal degeneration. The IgG1 subclass was present in all patients at their progressing stage but then disappeared at follow-up. Nerve pathology in the patients with anti-CNTN1 and anti-Caspr1 autoimmune nodopathies showed both structural changes in the paranodes and evidence of acute axonal degeneration. Renal biopsy specimens from two patients with membranous glomerulonephritis and anti-CNTN1 autoimmune nodopathy showed deposition of IgG1 and complement on the glomerular basement membrane, as well as IgG4. DISCUSSION: In patients with autoimmune nodopathies associated with anti-CNTN1 and anti-Caspr1 IgG4 antibodies, IgG1 subclass autoantibodies were present at their acute exacerbations and might have contributed to the axonal degeneration and glomerular injury. IgG1 disappeared with the cessation of disease progression, which indicates that the IgG1 subclass is a possible biomarker of disease activity.

Associations between the burdens of comorbid sleep problems, central sensitization, and headache-related disability in patients with migraine.

Objective: Sleep disturbances are common in migraine patients and affect quality of life. Central sensitization (CS) is likely to play a role in the increased severity and chronicity of migraine. We hypothesized that the number of comorbid sleep problems would affect headache-related disability through the effects of central sensitization (CS). Methods: We performed a cross-sectional study including 215 consecutive patients with migraine. Insomnia was defined as a Pittsburgh Sleep Quality Index (PSQI) global score greater than 5. Probable REM sleep behavior disorder (pRBD) was defined as an RBD screening score of 5 or greater. Excessive daytime sleepiness (EDS) was defined as an Epworth Sleepiness Scale score of 10 or higher. Suspected sleep apnea (SA) was defined as patients with snoring or sleep apnea witnessed 3 or more nights a week. CS was assessed by the Central Sensitization Inventory (CSI). Results: Restless legs syndrome, insomnia, EDS, SA and pRBD were observed in 25.6%, 71.6%, 34.4%, 10.2%, and 21.4%, respectively, of the patients. At least one sleep problem was present in 87.0% of the patients. According to the results of the multinomial logistic regression analysis with no sleep problems as a reference, after we corrected for adjustment factors, the Migraine Disability Assessment (MIDAS) score significantly increased when three or more comorbid sleep problems were present. According to our mediation analysis, an increased number of sleep problems had a direct effect on the MIDAS score after we adjusted for other variables, and the CSI score was indirectly involved in this association. Conclusion: The present study showed an association between migraine-related disability and the burden of multiple sleep problems, which was partially mediated by CS.

Could efficacy at 1 week after galcanezumab administration for patients with migraine predict responders at 3 months? A real world study.

BACKGROUND: In real-world studies, it is unclear whether galcanezumab has a significant effect in the first week after administration. METHODS: We retrospectively assessed 55 high-frequency episodic migraine (HFEM) and chronic migraine patients who received three galcanezumab doses. Mean changes in the numbers of weekly migraine days (WMDs) during month 1 and migraine days per month (MMDs) after 1-3 months of treatment were obtained. Clinical factors related to a ≥ 50% response rate (RR) at month 3 were analyzed. The prediction of ≥ 50% responders at month 3 using different weekly RRs at week 1 (W1) was evaluated. The RR at W1 was calculated with the following formula: RR (%) = 100 - [(WMDs at W1/baseline WMD) × 100]. RESULTS: The number of MMDs significantly improved from baseline to 1, 2 and 3 months. The ≥ 50% RR was 50.9% at 3 months. The number of WMDs decreased significantly from baseline to week 1 (- 1.6 ± 1.7 days), week 2 (- 1.2 ± 1.6 days), week 3 (- 1.0 ± 1.3 days), and week 4 (- 1.1 ± 1.6 days) during month 1. The RR at W1 was largest (44.6 ± 42.2%). The ≥ 30%, ≥ 50% and ≥ 75% RRs at W1 were significantly predictive of a ≥ 50% RR at 3 months. Logistic regression analysis predicting a ≥ 50% RR at month 3 showed that the RR at W1 was the sole contributing factor. CONCLUSION: In our study, galcanezumab showed a significant effect in the first week after administration, and the RR at W1 could predict the RR at 3 months.

The Effect of Rotigotine on Cognitive Function, Daytime Sleepiness, and Sleep Problems in Parkinson Disease: An Open-Label Pilot Study.

BACKGROUND: We hypothesized that rotigotine may have a positive effect on cognitive function in patients with Parkinson disease (PD) by improving daytime motor function and sleep status. METHODS: Fifteen PD patients with sleep disturbances, defined as a PD Sleep Scale (PDSS)-2 score of 15 or greater, were included in this single-center, 3-month open-label study. Participants received 2 to 4 mg/24 h (patch content: 4.5-9 mg) rotigotine for a 3-month period. At baseline and 3 months, the patients were evaluated on the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts III and IV and cognitive assessments, such as the Mini-Mental State Examination, frontal assessment battery, and Montreal Cognitive Assessment (MoCA). The Epworth Sleepiness Scale (ESS) and PDSS-2 were administered at baseline and at 1, 2, and 3 months. RESULTS: At 3 months, the MDS-UPDRS part III (-11.1, P < 0.0001) and MDS-UPDRS part IV (-1.1, P = 0.0013) scores significantly decreased, and off time significantly decreased (-34.6 minutes, P = 0.0085) from baseline. The PDSS-2 scores significantly decreased from baseline at 1 month (-4.2, P < 0.01), 2 months (-7.7, P < 0.0001), and 3 months (-7.3, P < 0.0001). The ESS also decreased at 1 month (-2.5, P < 0.05) and 3 months from baseline (-4.5, P < 0.01). The MoCA scores (1.6, P = 0.0029) significantly improved, but the Mini-Mental State Examination or frontal assessment battery scores did not significantly change. The mean changes from baseline to 3 months in the MoCA were negatively correlated with mean changes in the ESS scores. CONCLUSIONS: We suggest that rotigotine could improve cognitive function by improving motor symptoms, sleep disturbance, and daytime sleepiness in patients with PD.

Sleep-related hallucinations in patients with Parkinson's disease.

Given that sleep-wake cycle dysfunction can cause hallucinations in Parkinson's disease patients, sleep-related hallucinations may be a different subtype from hallucinations that occur only during full wakefulness. However, few studies that distinguish the onset situations of hallucinations related to sleep from those that occur in full wakefulness have been conducted to investigate hallucinations in Parkinson's disease patients. Therefore, we conducted a multicenter observational study to investigate the prevalence of and factors associated with sleep-related hallucinations in patients with Parkinson's disease. Information on hallucinations was collected by using a questionnaire and face-to-face interviews. Of 100 consecutive patients with Parkinson's disease, 29 (29%) reported sleep-related hallucinations, and 16 (16%) reported hallucinations only in the full wakefulness. A longer duration of Parkinson's disease treatment (OR 1.35, 95% CI 1.07 to 1.72), higher Beck Depression Inventory-II scores (OR 1.07; 95% CI 1.01 to 1.14), and higher rapid eye movement sleep behavior disorder scores (OR 5.60; 95% CI 1.54 to 20.38) were independent factors associated with the presence of sleep-related hallucinations in a multivariable analysis. Sleep-related hallucinations, but not daytime hallucinations, were associated with probable rapid eye movement sleep behavior disorder. Phenomenological discrimination between sleep-related hallucinations and daytime hallucinations is important for elucidating the full pathology in Parkinson's disease and the mechanisms underlying hallucinations.

Additional Steroid Therapy for Delayed Facial Palsy in Miller Fisher Syndrome.

Miller Fisher syndrome (MFS) is a variant of Guillain-Barré syndrome. Delayed facial palsy (DFP) is a symptom that occurs after other neurological symptoms begin to recover within four weeks from the onset of MFS. As there have been few detailed reports about DFP in MFS cases treated with additional immunotherapy, we investigated three cases of DFP in MFS treated with additional steroid therapies. The duration of facial palsy in our cases was 12-24 days. No severe adverse effects were observed. Although adverse side effects should be carefully monitored, additional steroid therapy might be a treatment option for MFS-DFP.

[A case of chronic and progressive distal symmetric type CIDP with subacute exacerbation: focus on clinical pattern of CIDP].

Chronic inflammatory demyelinating polyneuropathy (CIDP) is classified into typical type that is characterized by proximal weakness and atypical type that include demyelinating acquired distal symmetric (DADS) type. DADS type CIDP is characterized by slowly progressive clinical course, motor and sensory involvement dominant in the leg and resistance to therapy. We report the case of a 72 year-old man with DADS type CIDP, who have dysesthesia and weakness dominant in distal of limbs. Disease progression was resistant to therapy for prednisolone and intravenous immunoglobulin, but slowly progressive for 4 years. Subacute exacerbation that was accompanied by proximal weakness was occurred at 4 years later from onset. Nerve conduction study revealed markedly prolonged distal latencies and slowing of conduction velocities. Double filtration plasmapheresis improved symptom, after oral prednisolone kept remission. This case had characteristic of DADS type CIDP at the onset, but changed into typical CIDP also for the therapy in the clinical course. This case indicate the multiplicity of CIDP.

Impact of the COVID-19 Pandemic on the Quality of Life of Patients with Parkinson's Disease and Their Caregivers: A Single-Center Survey in Tochigi Prefecture.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the mental health of the general population. OBJECTIVE: We investigated the determinants of quality of life (QOL) in Parkinson's disease (PD) patients during the COVID-19 pandemic. METHODS: Impacts of lifestyle changes due to the COVID-19 pandemic on 100 patients with PD and their caregivers/spouses were assessed. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression. The physical component summary (PCS) and mental component summary (MCS) scores of the short form (SF)-8 were used to evaluate health-related QOL. RESULTS: Regarding health-related QOL, physical function, role physical, general health, vitality and the PCS score were significantly worse in PD patients than in caregivers. Worsening of PD-related symptoms, increased stress, and decreased physical activity were observed in 29.0%, 37.0% and 44.0% of PD patients, respectively. Sixteen patients (16.0%) experienced problems with hospital access, but none reported medication shortages. Strong concerns about COVID-19 were reported by 47.0% of caregivers and 50.0% of PD patients. In PD patients, increased gait disturbance and rigidity, disease severity, smoking, the levodopa equivalent dose and decreased body weight predicted a worse PCS score; anxiety, depression, female sex, stress and long disease duration predicted a worse MCS score. In caregivers, age and smoking contributed to a worse PCS score; depression, stress and worsening patient mood contributed to a worse MCS score. CONCLUSION: We report the negative impacts of the COVID-19 pandemic on health-related QOL and its determinants in PD patients and their caregivers.

Zonisamide effects on sleep problems and depressive symptoms in Parkinson's disease.

BACKGROUND: We aimed to evaluate the effect of zonisamide (ZNS) on motor symptoms and nonmotor symptoms such as depressive symptoms and sleep problems in Parkinson's disease (PD) patients with or without tremor. METHODS: We conducted a 3-month, open-label study to assess the effects of ZNS on motor symptoms, depressive symptoms and sleep problems. Twenty levodopa-treated PD patients with motor fluctuation completed the study. Patients received 25-50 mg/day of ZNS and were assessed for the Japanese version of the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts I, III, and IV, PD Sleep Scale (PDSS)-2, Beck depression inventory-2 (BDI-II), and PD Questionnaire (PDQ-8) at baseline and after 1, 2 and 3 months of treatment. Patients were categorized into the tremor group and nontremor group to assess changes in clinical parameters. RESULTS: At 3 months, the scores on the MDS-UPDRS parts I, III and IV significantly improved and off-time reduced compared to baseline. Additionally, the PDSS-2 total score significantly decreased at 3 months. Although there were no significant differences in changes in UPDRS part I, III, or IV between the groups after ZNS treatment, the tremor group had significant improvements in PDSS-2 at 3 months and BDI-II at 1, 2 and 3 months compared with the nontremor group. CONCLUSION: We showed the beneficial effects of ZNS on motor symptoms and sleep problems in levodopa-treated PD patients with motor fluctuation. ZNS may be more effective for several nonmotor symptoms in PD patients with tremor compared with those without tremor.

Bickerstaff's Brainstem Encephalitis Suspected as Functional Neurologic Disorders.

Functional neurologic disorders feature nervous system symptoms that cannot be explained by a neurological disease or other medical condition. The patient described here was a 21-year-old Japanese woman who was initially diagnosed with a functional neurologic disorder based on numbness and weakness of the limbs with no abnormalities in routine examinations. Further detailed examinations revealed monocytes in cerebrospinal fluid (CSF), and electroencephalography revealed widespread, low-voltage, slow waves with concentrated spindle waves. Thus, encephalitis was suspected, and steroid pulse therapy was initiated. Her symptoms subsequently improved. Afterward, CSF analysis was positive for serum anti-GQ1b IgG antibodies. We made a final diagnosis of Bickerstaff's brainstem encephalitis (BBE). Our report describes the difficult differentiation of functional neurologic disorders from BBE. Physicians and psychiatrists should be aware of BBE.

[Two adult patients with acute necrotizing encephalopathy following influenza virus infection].

Influenza encephalopathy is characterized by high fever, disturbance of consciousness following influenza virus infection. We encountered 2 adult patients with influenza-associated acute necrotizing encephalopathy (Case 1, a 70-year-old woman with diabetes; Case 2, a 49-year-old woman with multiple myeloma), showing hemorrhagic lesions in the bilateral thalamus. Case 1 presented with fever and disturbance of consciousness followed by status epilepticus, and Case 2 developed fever and drowsiness as initial manifestation. Influenza type A was positive in Case 1 and influenza type B was positive in Case 2. In the acute phase, 2 patients required respiratory ventilation and were treated with anti-influenza drug, steroid and immunoglobulin. Cognitive impairment remained in the both patients in the chronic phase. When acute necrotizing encephalopathy is suspected, intensive treatment should be started as early as possible to improve clinical outcome of patients.

Successful treatment of a 12-year-old boy with Guillain-Barré syndrome requiring tracheostomy due to respiratory muscle paralysis: A case report.

Childhood Guillain-Barré syndrome (GBS) occasionally leads to respiratory failure early after onset, requiring long-term ventilation management after tracheal intubation. However, patients requiring tracheostomy management are rare. In the present study, a case of a 12-year-old boy with GBS who required artificial respiration management due to rapid progression of respiratory muscle paralysis is reported. Intravenous immunoglobulin (IVIg) and pulse steroid therapy were provided; however, both were ineffective and tracheostomy was necessary 26 days after onset. A second course of IVIg and pulse steroid therapy was administered on day 34. With continued rehabilitation, the patient was able to walk long distances on day 74 and was subsequently discharged on day 89. In cases of severe GBS, when IVIg and pulse steroid therapy do not improve the respiratory muscle strength of the patient, early tracheostomy may improve the patient's quality of life during artificial respiration management.

Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers.

Voltage-gated Na+ (Na(v)) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Na(v) channel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Na(v) channel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Na(v) channels redistributed on both sides of affected nodes. These results suggest that Na(v) channel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.

Complement inhibitor prevents disruption of sodium channel clusters in a rabbit model of Guillain-Barré syndrome.

Complement-mediated disruption of voltage-gated sodium channels at the nodes of Ranvier acts in the development of acute motor axonal neuropathy. Nafamostat mesilate, a synthetic serine protease inhibitor, used in clinical practice for more than 20 years, has anti-complement activity. Acute motor axonal neuropathy rabbits obtained by GM1 ganglioside sensitization were or were not given nafamostat mesilate intravenously. Complement deposition and sodium channel disruption in the spinal anterior roots were significantly less frequent in the treated rabbits than in the controls. Nafamostat mesilate inhibited complement deposition and prevented sodium channel disruption. This provided the rationale for a clinical trial.

Delirium in two patients with Bickerstaff's brainstem encephalitis.

In this report, we describe the case of two patients with Bickerstaff's brainstem encephalitis (BBE) who developed delirium manifested as emotional incontinence, restlessness, and aggressive behavior from disease onset. Serum anti-GQ1b and anti-GT1a IgG antibodies were detected in both patients. When unusual psychiatric symptoms are observed, in addition to acute ophthalmoplegia and ataxia, neurologists should take into account the possibility of BBE. Brain MRI findings were normal in both patients and SPECT was performed on only patient 1. SPECT of patient 1 showed reversible hypoperfusion in the brainstem, bilateral thalami, and medial frontal lobe. Brain SPECT appears to be useful for detecting lesions of the brainstem as well as the basal ganglia or cerebrum in BBE.

[Case of Fisher syndrome following sphenoiditis].

Fisher syndrome is a subtype of Guillain-Barré syndrome that is characterized by the three chief symptoms of acute-onset external ophthalmoplegia, ataxia, and loss of tendon reflexes. Herein, we report a case of Fisher syndrome encountered by us,with sphenoiditis as the antecedent infection. The patient was a 39-year-old man who visited a local doctor after developing the symptom of rhinorrhea, followed three days later by diplopia. Cranial MRI suggested sphenoid sinusitis, and the patient was referred to our hospital with suspected rhinogenous intraorbital complication. Neurological findings included bilateral abduction deficit, which was considered unlikely to be an ocular manifestation of an intraorbital complication of right unilateral sphenoiditis. In addition, the reduction of the tendon reflexes in the limbs and ataxia suggested the diagnosis of Fisher syndrome, which was then confirmed based on the albuminocytologic dissociation observed on cerebrospinal fluid examination and a positive blood test result for anti-GQ1b antibody. The symptoms were attributed to the production of antibodies against antigens expressed on the oculomotor, trochlear, abducens and other nerves (anti-GQ1b antibody) due to the antecedent infection. The present patient was thought to have developed Fisher syndrome following sphenoiditis as an antecedent infection. Care must be taken to differentiate this condition from rhinogenous intraorbital complication.

[Oculomotor nerve compression on MRI in a 56-year-old man with pituitary apoplexy due to panhypophisitis].

A 56-year-old man noted sudden onset of headache, fever, right pupil-spared oculomotor nerve palsy and consciousness disturbance. Swelling of pituitary with T1 high intensity on brain MRI suggested the diagnosis of pituitary apoplexy. Considering significant decrease of pituitary anterior lobe hormone and central diabetes insipidus, high dose of hydrocortisone was administered. Eight days after onset, consciousness level and headache improved. On day 30, brain MRI revealed the reduction of mass size, and on day 46, photophobia and double vision disappeared. Following the rapid response to steroid and disappearance of pituitary lesion, pituitary apoplexy was probably caused by panhypophisitis. Thin-slice brain MRI confirmed the compression of oculomotor nerve at inlet zone of cavernous sinus, suggesting the mechanism of oculomotor palsy was perfusion impairment of feeding artery.