Severe cerebral involvement in adult-onset hemophagocytic lymphohistiocytosis

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) with cerebral involvement is challenging given the rarity of HLH and its resemblance to the much more common severe sepsis. Timely diagnosis and treatment may be lifesaving. We report two cases demonstrating different and rare forms of severe brain involvement in adult patients with HLH: acute necrotizing encephalopathy, and diffuse hemorrhagic disease due to disseminated intravascular coagulation. Severe HLH with brain involvement in adults is rare. HLH with cerebral involvement should be considered in patients presenting with severe systemic inflammatory response syndrome (SIRS) but negative cultures and unusual or unexpectedly severe clinical and/or radiologic signs of cerebral dysfunction. Similar brain injury may occur in patients with cytokine storm syndrome due to COVID-19.BackgroundHemophagocytic lymphohistiocytosis (HLH) presents with fevers, rash, organomegaly, cytopenia, and increased triglycerides and ferritin (Ramos-Casals et al., 2014) [1]. Neurologic abnormalities are reported in about one-third of patients (Cai et al., 2017), including a few cases of acute necrotizing encephalopathy (ANE) (Xiujuan et al., 2015). Coagulation abnormalities are frequent in HLH patients (Valade et al., 2015).ObjectiveTo raise awareness about the importance of early diagnosis and treatment of HLH with neurological involvement to prevent serious complications and demise.     

Demyelinating peripheral neuropathy associated with hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study

We report the case of an 11-year-old male who developed subacute diffuse polyradiculoneuropathy, associated with digestive symptoms and Epstein-Barr virus infection. Parental consanguinity was present. The laboratory findings including bone marrow smear were consistent with hemophagocytic lymphohistiocytosis (HLH). Electrophysiological study of peripheral nerves revealed an intense and diffuse demyelinating process. The histological nerve lesions were severe and purely demyelinating. Most axons were intact. There was a diffuse infiltration of the nerve parenchyma by mononuclear cells. Immuno-electron microscopic study evidenced entry of macrophages into Schwann cell cytoplasm with dissociation of myelin sheaths. This boy died several months after the onset of the neuropathic symptoms. HLH is a rare genetic or acquired disorder in childhood characterized by abnormal immune activation, which induces an uncontrolled inflammatory response with sustained hyperactivation of T lymphocytes and macrophages. Only very rare cases of peripheral nerve involvement have been described in HLH. This is the first case showing that peripheral nerves, as other viscera, may be destroyed by the macrophagic infiltration, which characterizes HLH.     

Acute encephalopathy as a primary manifestation of haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is characterized anatomically by an infiltration of multiple tissues with lymphocytes and haemophagocytic histiocytes. First symptoms are usually hepatosplenomegaly, pancytopenia, and intractable fever. Up to 73% of those with HLH develop CNS involvement during the disease course. The peculiarity of the two patients presented here, a 20-month-old Italian female and a 4-year-old Moroccan female, is that the initial presenting neurological symptoms mimicked an encephalitis, anticipating the typical systemic symptoms by 1 and 4 months. They developed progressive encephalopathy accompanied by status epilepticus, one child developed a secondary hydrocephalus. In both children it was not possible to detect an underlying infection or malignant disease and there were no other cases in the family that suggested a familial form of HLH. Diagnosis and initiation of treatment was delayed because of the initial encephalopathic clinical picture and the late onset of the typical systemic features. As early diagnosis allows better therapeutical approaches, haemophagocytic lymphohistiocytosis should be considered in children with persistent or progressive findings of encephalopathy, especially in the absence of identification of a plausible pathogen.     

Neuropsychological Assessment in a Case of Adult-Onset Hemophagocytic Lymphohistiocytosis (HLH)

We present a case of an individual diagnosed with hemophagocytic lymphohistiocytosis (HLH), an extremely rare and commonly fatal disorder characterized by rapid dysregulation of immune system processes. Typical age of onset is in childhood, with adult-onset occurring less frequently. The pathophysiology of this condition is characterized by a hyperinflammatory response with infiltration of visceral organs, lymph nodes, bone marrow, and the central nervous system. The clinical presentation has been documented in the extant medical literature. However, there appear to be no published reports of neuropsychological functioning in HLH patients. The patient we present here is a 28-year-old woman with 16 years of education who developed HLH subsequent to systemic lupus erythematosus flare-up. She was initially comatose for 3 weeks. Acute MRI reported multiple subcortical abnormalities, including the brainstem. The patient underwent chemotherapy, immunosuppresant, and steroid treatments. She underwent a neuropsychological evaluation at 2.5 and 7 months post initial presentation. Preliminary neuropsychological evaluation found impairments in motor abilities and aspects of executive functions. Subsequent evaluation showed improved executive function and relative sparing of higher-order cognitive abilities, but continued impairment on motor tests. To our knowledge this is the first study to report neuropsychological data for an adult diagnosed with HLH.     

Neuropsychological Assessment in a Case of Adult-Onset Hemophagocytic Lymphohistiocytosis (HLH)

We present a case of an individual diagnosed with hemophagocytic lymphohistiocytosis (HLH), an extremely rare and commonly fatal disorder characterized by rapid dysregulation of immune system processes. Typical age of onset is in childhood, with adult-onset occurring less frequently. The pathophysiology of this condition is characterized by a hyperinflammatory response with infiltration of visceral organs, lymph nodes, bone marrow, and the central nervous system. The clinical presentation has been documented in the extant medical literature. However, there appear to be no published reports of neuropsychological functioning in HLH patients. The patient we present here is a 28-year-old woman with 16 years of education who developed HLH subsequent to systemic lupus erythematosus flare-up. She was initially comatose for 3 weeks. Acute MRI reported multiple subcortical abnormalities, including the brainstem. The patient underwent chemotherapy, immunosuppresant, and steroid treatments. She underwent a neuropsychological evaluation at 2.5 and 7 months post initial presentation. Preliminary neuropsychological evaluation found impairments in motor abilities and aspects of executive functions. Subsequent evaluation showed improved executive function and relative sparing of higher-order cognitive abilities, but continued impairment on motor tests. To our knowledge this is the first study to report neuropsychological data for an adult diagnosed with HLH.     

A case of acute encephalopathy with hemophagocytic lymphohistiocytosis and clonal T-cell expansion

We report on a 9-year-old boy who presented with acute encephalopathy and hemophagocytic lymphohistiocytosis (HLH). The patient was referred to our hospital because of fever, seizures, and decreased consciousness. He showed moderately elevated levels of proinflammatory cytokines in the cerebrospinal fluid and plasma, and clonal expansion of highly activated CD8⁺ T cells in the peripheral blood. These CD8⁺ T cells were found to be larger cells that stained positive for T-cell receptor Vβ13.6, and decreased shortly after steroid therapy. Our findings suggest that his acute encephalopathy was likely a clinical manifestation of HLH, and that immunophenotypic analysis may be helpful for early recognition of HLH in such rare encephalopathy.     

Hemi-meningitis with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare lymphoproliferative disorder. HLH may occur as a complication of Epstein-Barr virus (EBV), particularly in patients with immunodeficiencies. Herein, we describe a 16-year-old girl with neurological complications associated EBV-induced HLH. Her cerebral magnetic resonance imaging (MRI) showed contrast-enhanced axial T1-weighted images with enhancement of meningeal surface in the right hemisphere that was consistent with right hemi-meningitis. Hydrocephalus, dilated subdural spaces, delayed myelination, edema, diffuse parenchymal atrophy, calcifications, diffuse/patchy white matter abnormalities have all been previously described with HLH. To the best of our knowledge, this is the first case of hemi-meningitis associated with HLH. We suggest that clinicians should consider HLH with vascular disorders when they determine unilateral meningitis on a brain MRI.     

Intravascular lymphoma presenting as a longitudinally-extensive myelitis: diagnostic challenges and etiologic clues

Intravascular lymphoma is a rare disorder that commonly involves the central nervous system. Neurologic involvement may be the presenting and only manifestation. Identifying intravascular lymphoma as the cause of neurologic disease is diagnostically challenging. We report an elderly woman presenting with subacute onset paraparesis due to spinal cord involvement by an intravascular lymphoma. Progressive worsening was associated with extension of a longitudinally-extensive thoracic intramedullary spinal cord lesion. Extensive investigations failed to provide a diagnosis in life and repeated empiric therapeutic trials were unsuccessful. Diagnostic confirmation was postmortem. A longitudinally-extensive spinal cord lesion has a broad differential diagnosis. Intravascular lymphoma should be considered particularly in older individuals. The presence of coexisting hematologic abnormalities should prompt consideration of a bone marrow biopsy. Early diagnosis may direct therapy and lead to a more favorable prognosis.     

Intramedullary Sarcoidosis Presenting with Delayed Spinal Cord Swelling after Cervical Laminoplasty for Compressive Cervical Myelopathy

Sarcoidosis is a systemic disease of unknown etiology that may affect any organ in the body. The nervous system is involved in 5-16% of cases of sarcoidosis. Here, we report a case of intramedullary sarcoidosis presenting with delayed spinal cord swelling after laminoplasty for the treatment of compressive cervical myelopathy. A 56-year-old woman was admitted to our hospital complaining of upper extremity pain and gait disturbance. The patient had undergone laminoplasty for compressive cervical myelopathy 3 months previously. Follow-up magnetic resonance imaging revealed a large solitary intramedullary lesion with associated extensive cord swelling, signal changes, and heterogeneous enhancement of spinal cord from C2 to C7. Spinal cord biopsy revealed non-necrotizing granulomas with signs of chronic inflammation. The final diagnosis of sarcoidosis was based upon laboratory data, imaging findings, histological findings, and the exclusion of other diagnoses. Awareness of such presentations and a high degree of suspicion of sarcoidosis may help arrive at the correct diagnosis.     

On the mechanisms and diagnosis of conduction disturbances due to demyelination with special reference to multifocal demyelinating neuropathy (Lewis-Sumner)

Multifocal demyelinating neuropathy with persistent conduction block can mimic motor neuron disease, but is potentially reversible. Its diagnosis rests upon electrophysiological demonstration of focal conduction block at multiple sites. Conduction block is the most important mechanism causing clinical symptoms in peripheral nerve demyelination. On the other hand, conduction slowing is not always associated with clinical symptoms. In 2 out of 9 patients with multifocal demyelinating motor neuropathy, MRI showed focal swelling of the nerve at the site of conduction block. Both of them had elevated titers of anti-GM1 antibodies. In one, we biopsied a portion of the medial pectoral nerve, which was adjacent to the focal swelling, at surgical exploration. Pathological findings included very thin myelin associated with large diameter fibers and small onion bulb formation, suggesting that remyelinative process is abortive in this disease leading to persistent conduction block. Anti-GM1 antibodies bound to the denuded axoplasmic membrane may interfere with the process by masking the cell surface markers. The reason why the sensory fibers are spared is unclear, but it may be possible that GM1 in sensory axons have less affinity to the antibody than that in motor fibers.     

Gaucher disease: Unusual presentation and mini-review

We aim to describe an 8-year-old boy with an unusual clinical presentation of Gaucher disease (GD). Gaucher disease is a progressive lysosomal storage disorder due to deficiency of the specific enzyme glucocerebrosidase with varying clinical features, but often involving the monocytes-macrophages systems. This child ran a progressive course with a devastating outcome. Three distinct GD subtypes have been described with varying clinical features based on the presence or absence of neurologic involvement. Gaucher disease diagnosis is obtained via: enzyme activity assay, gene mutation study, bone marrow aspiration in addition to multiple other tests that have been successfully used in diagnosis of cases of GD. Treatment modalities include enzyme replacement treatment, substrate reduction therapy, bone marrow transplantation, blood transfusion, and surgery are available management modalities for GD. Gaucher disease is a chronic disease requiring a multidisciplinary team approach with regular follow up with multiple subspecialties.Gaucher disease (GD) was initially described by Philippe Gaucher more than 2 centuries ago, in his doctoral thesis in 1882, when he hypothesized that infiltration of enlarged cells in a spleen represented a “neoplasm.” The biochemical basis for GD was elaborated 83 years later (1965) by Roscoe Brady’s group at the National Institutes of Health. The molecular basis of the disease was elucidated in the late 1980s, when the glucocerebrosidase gene mutations were identified.1 Gaucher disease is characterized by a range of phenotypes, from a perinatal lethal form to an asymptomatic form; however, 3 distinct clinical types have been recognized based on the disease progression and the presence or absence of neurologic involvement.2 Unusual presentation should not be overlooked in this potentially treatable disease, as it may have a positive impact on the disease prognosis and quality of life in the patient.3 Gaucher disease can be diagnosed through enzyme activity assay (EAA), molecular diagnosis, bone marrow aspiration (BMA), and other tests.4,5 Treatment modalities for GD include enzyme replacement treatment (ERT), substrate reduction therapy (SRT), bone marrow transplantation, surgery, and blood transfusion in selected cases.6,7 We aim to describe an 8-year-old boy from consanguineous parents; he had a history of recurrent pyrexia of unknown origin, with equivocal investigations. Raising awareness of early diagnosis of such cases and consideration of unusual presentations of rare diseases can have a positive impact on the progress and long-term management of such cases.     

Progressive myoclonic epilepsy due to Gaucher''s disease in an adult.

A 39 year old Jewish male with a 22 year history of progressive myoclonic epilepsy was found to have Gaucher cells in his sternal bone marrow. The diagnosis of Gaucher's disease was confirmed by the demonstration of beta-glucosidase deficiency in fibroblasts. Although neurological involvement is extremely rare in adults with Gaucher's disease, this disease is another lipidosis which should be considered in patients with progressive myoclonic epilepsy.     

Possible use of CSF glycosphingolipids for the diagnosis and therapeutic monitoring of lysosomal storage diseases.

We used a high-performance liquid chromatography method to measure CSF gangliosides, neutral glycolipids, and sulfatides in patients with lysosomal storage disorders. These measurements could be done on less than 1 milliliter of CSF. In patients with GM1 gangliosidosis, GM1 ganglioside was increased, and in GM2 gangliosidosis patients, GM2 ganglioside was increased in CSF. Sulfatides were variably increased in CSF early in the course of the disease and appeared to be a means of monitoring patients, following bone marrow transplantation. Fabry's disease patients showed an increase in globotriaosylceramide, but Krabbe's disease patients did not demonstrate an increase in galactosylceramide. This study suggests that CSF glycosphingolipid measurements may prove helpful in the diagnosis and monitoring of lysosomal storage diseases.     

Maladie de Niemann-Pick type “C” de Crocker

Summary The authors report electron microscopic findings in brain, bone marrow and liver biopsies in a case of juvenile Niemann-Pick disease (Crocker's type C). The diagnosis was supported by clinical data increase of blood sphingomyelin and vacuolated histiocytes in bone marrow and liver. Neurons and glial cells were filled with two types of cytosomes: classical multilamellar bodies and unusual pleiomorphic bodies. The latter type probably showed some lipofuscinic component. The relationship between type C and classical Niemann-Pick disease is discussed.

     

Neuroimaging in brain swelling

Modern neuroimaging techniques have added to the understanding of brain edema and its earlier diagnosis. It is now possible to quickly know whether a lesion is focal with associated pressure effects or whether the symptoms are due to a diffuse process whose treatment may be different. The various herniation syndromes can be appreciated on the CT without risk to the patient. The neuropathologic proof of earlier pathophysiologic theories of three types of edema (vasogenic, cytotoxic, and interstitial) caused by various diseases need no longer wait for the autopsy specimen; it is strongly suggested by modern neuroimaging techniques. Some disease entities (meningitis, trauma, ischemic infarction) are characterized by several types of edema, depending on when the patient is examined. Swelling of the brain is an important topic to study not only because it is common, but also because it may be fatal. Neuroimaging in brain swelling has led to new knowledge regarding this important subject. This review is primarily that of the computerized tomogram in diagnosing both focal and diffuse swelling of the brain and some basic understanding pathophysiologically that would allow one to explain the image obtained. Because edema is primarily water, it seems likely that magnetic resonance imaging will shed even further light on this intriguing subject.     

Intracranial localization revealing Hodgkin's disease

The central nervous system's (CNS) involvement is uncommon in Hodgkin's disease (HD) and usually occurs in patients with relapsing disease many years after the initial diagnosis. An isolated involvement of the CNS is extremely rare and therefore, difficult to diagnosis. We report the case of a 27-year-old woman with seizure and a left cerebrodural mass on the cerebral imaging; secondarily, she developed cervical lymph node swelling; histological examination of the node revealed HD of the nodular sclerosis type. The dural lesion resolved after chemotherapy for HD.     

Muscle-specific kinase antibody associated myasthenia gravis after bone marrow transplantation

Myasthenia gravis is a rare complication of bone marrow transplantation and graft versus host disease. We report a 30-year-old woman presented with oculobulbar and proximal limb weakness after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Also, she developed graft versus host disease following bone marrow transplantation. Investigations led to the diagnosis of muscle specific kinase antibody related myasthenia gravis. There have been only two case reports of muscle specific kinase antibody positive myasthenia gravis after bone marrow transplantation in the literature, but none of the previously reported cases had graft versus host disease.     

股骨上端骨髓水肿综合征10例临床及影像学分析

背景：股骨上端骨髓水肿综合征为自限性疾病，具体的发病机制尚未完全明确，因此目前临床上没有明确的治疗措施，主要以对症处理为主，不遗留严重后遗症。 目的：分析股骨上端骨髓水肿综合征的病因、临床表现、影像学特点及其与股骨头缺血性坏死的关系和区别。 方法：收集2007-09/2010-05在苏州大学附属第一医院门诊以股骨头缺血性坏死首诊，后确诊为股骨上端骨髓水肿综合征患者，共10例11髋(男5例，女5例)为研究对象，均采取门诊治疗，急性期减少患肢活动量，避免患肢过度负重，有长期饮酒史患者，劝其戒酒，疼痛较重患者口服非类固醇抗炎止痛药物等治疗，原有基础疾病继行相关治疗，定期门诊随访，影像学复查。 结果与结论：全部病例经治疗后临床症状明显改善，未有不良后遗症。X射线平片示股骨头形状完整，关节面无塌陷，治疗前MRI图像显示的T1像加权低信号，T2加权或STIR成像上高信号的现象于治疗后消失，其预后与股骨头缺血性坏死有明显区别。提示股骨上端骨髓水肿综合征是一种致病原因复杂的自限性疾病，应了解其临床特征，明确诊断，避免误诊，选择正确的治疗方案。     

POEMS综合征8例临床分析

目的探讨POEMS综合征发病机制及临床特征，提高对POEMS综合征的诊治水平。方法分析8例POEMS综舍征的一般资料、临床表现、相关的辅助检查、治疗及预后，并结舍文献进行讨论。结果本病是累及多系统的疾病，以周围神经病最具有特征性，肝、脾和（或）淋巴结肿大，内分泌的病变，皮肤改变，水肿及骨髓浆细胞增多比较常见。治疗以激素、免疫抑制剂为主，可结合抗雌激素、放疗的方法，预后差。结论POEMS综合征与浆细胞病关系密切，累及多系统的病变，临床表现复杂多样，应注意多系统的检查，提高临床的诊断水平。     

Manganese induces cell swelling in cultured astrocytes

Manganese in excess is neurotoxic and causes a CNS disorder that resembles Parkinson's disease (manganism). Manganese highly accumulates in astrocytes, which renders these cells more vulnerable to its toxicity. Consistent with this vulnerability, manganese has been shown to cause histopathological changes in astrocytes (Alzheimer type II change), generates oxidative stress and bring about mitochondrial dysfunction, including the induction of the mitochondrial permeability transition (mPT) in astrocytes. In addition to manganism, increased brain levels of manganese have been found in hepatic encephalopathy, a chronic neurological condition associated with liver dysfunction, wherein Alzheimer type II astrocytic changes are also observed. As low-grade brain edema, possibly secondary to astrocyte swelling, has been reported in hepatic encephalopathy, we hypothesized that manganese may contribute to such edema. We therefore exposed cultured astrocytes to manganese (Mn(3+)) acetate (25 and 50microM) for different time periods and examined for changes in cell volume. Manganese dose-dependently induced astrocyte swelling; such swelling was first observed at 12h (28%), which further increased (54%) at later time points (24-48h). Pretreatment of astrocyte cultures with antioxidants, including vitamin E, the spin trapping agent PBN, and the iron-chelating agent desferroximine, as well as the nitric oxide synthase inhibitor l-NAME, all significantly blocked (50-80%) astrocyte swelling caused by manganese, suggesting that oxidative/nitrosative stress is involved in the mechanism of such swelling. Cyclosporin A, an inhibitor of mPT also blocked (90%) manganese-induced astrocyte swelling. The data indicate that manganese exposure results in astrocyte swelling and such swelling, at least in part, may be caused by oxidative stress and/or mPT. Astrocyte swelling by manganese may represent an important aspect of manganese neurotoxicity, and may be a factor in low-grade brain edema associated with chronic hepatic encephalopathy.