[A patient with relapsing-remitting multiple sclerosis who relapsed frequently and developed primary biliary cholangitis after pregnancy and discontinuation of fingolimod].

We present the case of a 37-year-old woman who was diagnosed as having relapsing-remitting multiple sclerosis (MS) when she was 25 years old. She remained relapse-free after she was started on treatment with oral fingolimod. However, at the age of 35, when she became pregnant, fingolimod was discontinued, and she began to suffer from frequent relapses. Following her delivery, she was started on treatment with dimethyl fumarate. Subsequently, with elevation of the serum levels of hepatobiliary enzymes and peripheral blood eosinophil count, possibly caused by dimethyl fumarate, her treatment was switched back to fingolimod. However, the elevation of the serum hepatobiliary enzyme levels and peripheral blood eosinophil count persisted. A serological test for autoantibodies revealed the diagnosis of primary biliary cholangitis (PBC). Pregnancy or discontinuation of fingolimod could have influenced the immune status of the patient and worsened the state of MS. There are some reports of autoimmune hepatic diseases, including PBC, being caused by disease modifying drug (DMD), like interferon-ß or even steroid pulse therapy, although the underlying mechanisms remain unknown. This risk should be borne in mind when treating patients with MS, especially younger women, with DMD.

Two Medullary Hemorrhage Cases Complicated by Respiratory Distress in the Early Phase.

Medullary hemorrhage is quite rare among brain stem hemorrhage cases, thus the clinical course remains unclear. In the medulla oblongata, respiratory centers are located and previous reports indicate that medullary lesions have possible relationship with acute respiratory distress syndrome. This kind of respiratory failure is commonly caused by neurogenic pulmonary edema (NPE), which is defined as noncardiac noninfectious acute respiratory distress syndrome with changes in intracranial condition including cerebrovascular events. However, to date, very few reports have described cases with medullary hemorrhage accompanied by NPE. We experienced 2 patients with medullary hemorrhages. A 65-year-old man presented with sudden onset of headache, whose head computed tomography showed right medullary hemorrhage. Another 76-year-old woman was transferred because of sudden limb weakness and diagnosed with left medullary hemorrhage. Digital subtraction angiography showed the presence of arteriovenous fistula in the medulla oblongata and drainer veins in the second case. Both cases were complicated by acute pulmonary edema in the early phase, suggesting the possible association of the medullary hemorrhage with NPE.

Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.

OBJECTIVE: To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan. METHODS: We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used. RESULTS: There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity. CONCLUSIONS: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.

A case of myasthenia gravis and myositis induced by nivolumab.

A 74-year-old woman, who developed advanced colon cancer with focal recurrence, received two courses of a low dose of nivolumab. Five days after the second course she noticed bilateral ptosis. Her symptoms rapidly progressed to generalized manifestations including limb and neck weakness, dyspnea, and myalgia within the following two weeks. Neurological and laboratory findings supported the diagnosis of myasthenia gravis and myositis induced by nivolumab. The combination immunotherapy including oral prednisolone, intravenous immunoglobulin and plasma exchange with noninvasive positive-pressure ventilation successfully avoid tracheal intubation. Nivolumab, one of the immune checkpoint inhibitors, is the anti-programmed cell death-1 (PD-1) protein monoclonal antibody, which is effective for various cancers. Since the immune checkpoint inhibitors are going to be used widely, it is important to recognize the specific subtype of myasthenia gravis for neurologists.

[Neurological Signs and Symptoms of True Neurogenic Thoracic Outlet Syndrome].

Thoracic outlet syndrome (TOS) is a well-known disorder, but many aspects of its pathology, including its definition, has been disputed. True neurogenic TOS (TN-TOS) is a rare but well-defined clinical condition. TN-TOS results from the compression of the C8/T1 roots (dominant for the T1 root) or the proximal lower trunk of the brachial plexus by a fibrous band. The band extends from the first rib to either the tip of an elongated C7 transverse process or a rudimentary cervical rib. The most common presenting symptoms of TN-TOS are insidious-onset atrophy and weakness of the intrinsic hand muscles, predominantly in the thenar eminence and radial digit flexors. Nerve conduction studies demonstrate pathognomonic findings: severely attenuated compound muscle action potential of the abductor pollicis brevis muscle, and usually, loss of the sensory nerve action potential of the medial antebrachial cutaneous nerve. Numbness and sensory loss are typically observed, mainly in the medial forearm, although they are usually mild, and may be absent in some patients. Severe pain or paresthesia proximal to the elbow is not observed. The classical concept of TOS underlie nonspecific neurogenic TOS. It has been primarily diagnosed using provocative maneuvers. However, there is controversy regarding its pathological conceptualization and existence, as objective evidence of the disease is still lacking.

C8 and T1 innervation of forearm muscles.

OBJECTIVE: C8-dominant innervation of ulnar-innervated and T1-dominant innervation of median-innervated intrinsic hand muscles have been suggested, although less is known regarding forearm muscles. We aimed to determine myotomal innervation of the forearm muscles based on the clinical and electromyographial findings of patients with C8 or T1 lesions. METHODS: Medical Research Council scale and EMG findings were retrospectively reviewed in 16 patients with C8 lesions (2 postmedian sternotomy C8 plexopathy and 14 C8 radiculopathy) and 9 patients with T1-dominant lesions (8 true neurogenic thoracic outlet syndrome and 1 T1 radiculopathy). RESULTS: Clinical and EMG findings revealed T1-dominant innervation of the flexor digitorum superficialis, flexor digitorum profundus of the index finger, abductor pollicis brevis, and flexor pollicis longus muscles, and C8-dominant innervation of the flexor carpi ulnaris, flexor digitorum profundus of the little finger, and digit extensors innervated by the posterior interosseous nerve. The first dorsal interosseous, and abductor digiti minimi muscles seem to be innervated by both C8 and T1 roots. CONCLUSIONS: C8-dominant innervation of ulnar-innervated muscles and T1-dominant innervation of median-innervated muscles are also evident for forearm flexor muscles. SIGNIFICANCE: Such an additional evidence for myotomal innervation will improve localization in clinical as well as electrophysiological diagnoses.

Burden of overactive bladder symptom on quality of life in stroke patients.

AIMS: Overactive bladder (OAB) affects the daily life of many stroke victims. In contrast to urinary incontinence, little is known about the prevalence and risk factors for OAB among stroke patients. Therefore, we conducted a questionnaire survey and analyzed the results together with the clinical data and MRI findings. METHODS: A total of 500 volunteer patients with chronic-phase stroke were enrolled. The overactive bladder symptom score (OABSS), Short Form 8 (SF-8) health survey questionnaire, and some key international questionnaires about urinary dysfunction were assessed. RESULTS: We diagnosed 141 patients (28%) with OAB, among whom 103 (73%) had never been treated for their symptoms. Patients with OAB showed lower scores in both the physical and mental components of the SF-8, which suggested the burden of OAB on the quality of life of stroke patients. Advanced age and male gender were closely related to high OABSS. The modified Rankin Scale (mRS) was positively correlated with OABSS. Patients with cerebral infarction and those with intracerebral hemorrhage showed a similarly high OABSS. The severity of deep white-matter hyperintensity on MRI, classified by the 4-grade Fazekas scoring system, was significantly associated with high OABSS irrespective of presence of accompanying infarcts. Patients with cerebral infarcts in the region of anterior circulation showed a higher OABSS than those with cerebral infarcts in the posterior circulation. CONCLUSIONS: Based on the present risk analysis, patient care should be preferentially focused on the detection and treatment of OAB to improve the quality of life of stroke patients.

[Disturbance in neurovascular unit plays a pivotal role in pathophysiology of small vessel disease in the brain].

Among many conditions causing small vessel diseases, lipohyalinosis is the leading pathology next to microatheroma. Lipohyalinosis affects penetrating arteries distally than microatheroma. Proliferation of smooth muscle cells may occlude the lumen, reducing the blood flow and inducing lacunar infarction. In contrast, fibrinoid necrosis of smooth muscle cells in the media may weaken the vascular constriction, increasing the perfusion pressure in the capillary and damaging the blood brain barrier which can induce white matter lesion. Neurovascular unit (NVU) is a concept that neurons, astrocytes, and vessels function as a unit to support neuronal activity. NVU is involved in the maintenance of synapse, transmitter, energy metabolism, blood-brain barrier, and blood flow. Change in neuronal activity is transmitted to capillaries through NVU, where the information is collected along vessels proximally and regulates blood flow (proximal integration model). CARASIL and CADASIL both affect vascular smooth muscle cells, resulting in vascular dilatation, damaging NVU, and inducing white matter lesion. Occlusion of the affected vessels, causing cerebral ischemia, under these diseases is relatively infrequent. Similarity in pathophysiology between hypertensive arteriolar disease and the familial angiopathy may indicate that injury to NVU may indicate the common pathophysiology of white matter lesions.

Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model.

Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke.

[Role of T lymphocytes in ischemic brain injury].

Recently, inflammation has been implicated in the progression of cerebral ischemic injury. Especially, T lymphocytes have been shown to infiltrate into the ischemic brain 24 hours after the onset, however, the function and specific subpopulation of these infiltrated T lymphocytes have not been fully understood. By using cytokine-deficient mice with transient focal ischemia model, we have shown that IL-23 and IL-17 but not IL-6 or IFN-γ play pivotal roles in the ischemic brain injury. We found that IL-23, which was mainly produced from infiltrated macrophages, induced IL-17-producing T lymphocytes in the ischemic brain. IL-23 and IL-17 expression increased 1 day or 3 day after ischemic injury, respectively, and promoted inflammatory responses by increasing the expression of neurotoxic factors. To our surprise, IL-17 was mainly produced by γδT lymphocytes, but not helper T cells. Based on these findings, we have tried to develop new therapeutic strategy for the progression of brain infarction. We found that administration of FTY720 (Fingolimod) and antibody against γδT lymphocytes attenuated ischemic brain damage. Furthermore, antibody against p40 which neutralizes both IL-23 and IL-12 simultaneously was also effective. Therefore, anti-cytokine therapy will be applicable for neuroprotection in the delayed phase of brain ischemia.