Klemens Angstwurm

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response

Objective To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD). Design This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes. Results 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065). Conclusions Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission (p = 0.003) and better response to high-dose intravenous steroids (p = 0.005) compared to woman at >40 years. Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.

Activation of TGF-β-induced non-Smad signaling pathways during Th17 differentiation

Although transforming growth factor‐β (TGF‐β) has been shown to positively regulate the development of murine T helper type 17 (Th17) cells, which of the intracellular signaling pathways are involved is controversial. We examined Smad‐dependent and ‐independent signaling molecules downstream of the TGF‐β receptor (TGFβR) involved in Th17 differentiation of naive murine CD4+CD62L+ T cells. During Th17 differentiation of wild‐type T cells, Smad2/3 was phosphorylated, indicating activation of the canonical Smad pathway. T cells lacking TGFβRII did not differentiate into Th17, whereas T cells treated with a TGFβRI kinase inhibitor (SB‐431542) or overexpression of inhibitory Smad7 retained a low amount of Th17 polarization despite absent Smad2/3 phosphorylation. Using protein antibody arrays we found an increase of expression and phosphorylation of the following Smad‐independent signaling molecules in Th17‐polarized wild‐type T cells: AKT1(Tyr474), AKT2 (Ser474), ERK1‐p44/42 MAPK(Tyr204), mTOR(Thr2446), p38 MAPK(Thr180), Rac1/cdc42(Ser71), SAPK/JNK(Tyr185) and SP1(Thr739). Pharmacological inhibition of AKT/mammalian target of rapamycin (mTOR) signaling with rapamycin or LY294002 decreased Th17 differentiation of wild‐type T cells, and completely abolished interleukin‐17 production in T cells with overexpression of Smad7. Rapamycin and LY294002 also decreased induced regulatory T cell differentiation, but only had minor additive effects to Smad7 overexpression. Finally, inhibitors of mitogen‐activated protein kinase (MAPK) blocked in vitro polarization of Th17 cells. Our data show that Smad‐dependent and ‐independent intracellular pathways contribute to murine Th17 differentiation.

Muscle cramps and neuropathies in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease.

Objective Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. Methods In a single-centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical, laboratory and neurophysiological findings were evaluated by descriptive statistics and regression analysis to detect factors associated with muscle cramps. Patient’s sera were examined for anti-neuronal antibodies. Results Nine patients had polyneuropathy, 4 had muscle cramps, and 14 had both. Median onset of polyneuropathy and muscle cramps was 6 and 9 months after allogeneic hematopoietic stem cell transplantation, respectively. Neurophysiology revealed a predominantly axonal polyneuropathy in 20 of 26 patients. In 4 of 19 patients electromyography showed signs of myopathy or myositis. Muscle cramps were more frequent during chronic than acute GVHD and affected muscles other than calves in 15 of 18 patients. They typically occurred daily, lasted 1 to 10 minutes with medium to severe pain intensity, compromised daily activity or sleep in 12, and were refractory to therapy in 4 patients. Muscle cramps were less likely with tacrolimus treatment and signs of severe polyneuropathy, but more likely with myopathic changes in electromyography and with incipient demyelinating polyneuropathy, shown by increased high frequency attenuation of the tibial nerve. Serological studies revealed antinuclear or antimitochondrial antibodies in a subset of patients. Two of 16 patients had a serum reactivity against peripheral nervous tissue. Conclusion Muscle cramps are associated with chronic GVHD, often compromise daily activity, and correlate negatively with axonal polyneuropathy and positively with myopathy and incipient demyelination.

Progressive external ophthalmoplegia as initial manifestation of sporadic late-onset nemaline myopathy.

Sporadic late-onset nemaline myopathy (SLONM) is a rare disease and typically presents in patients older than 40 years with slowly progressive weakness in a limb-girdle distribution and unremarkable family history [1, 2]. Serum creatine kinase is usually normal, and electromyography may show myopathic changes. Nemaline rods in affected muscle fibers are considered the histopathological hallmark of nemaline myopathy and are mainly found within the sarcoplasm, inside of myonuclei, or both [3]. Ocular involvement has never been described in a patient with SLONM. We report a patient with SLONM suffering from prominent involvement of external ocular muscles. A 60-year-old female patient was reexamined for a chronic progressive oculopharyngeal syndrome that was present for 6 years. Initial symptoms were double vision and ptosis, followed by weakness of eye-closure. Two years after the onset of symptoms, she presented an exclusive picture of external ophthalmoplegia. During the following years she was unable to open or close her eyes voluntarily, lost her ability to whistle or smile, developed a hoarse voice and swallowing difficulties. There was no diurnal variation of symptoms, or fatigability. Family history for neuromuscular diseases was unremarkable. On examination she had complete bilateral ptosis and palsy of extraocular muscles, while pupillar size and pupillar reactions to light and accommodation were normal. She had a myopathic face with atrophy of masseter and temporalis muscles, severe bilateral facial palsy, and severe dysphonia. Strength was MRC grade 4 for neck flexion, head rotation, and neck extension. Further neurological examination was normal, notably fundoscopy and proximal and distal limb strength. Laboratory examinations provided normal values for standard parameters, serum creatine kinase, a comprehensive panel of autoimmune antibodies, including antibodies against acetylcholine receptor or muscle-specific kinase, anti-HIV 1/2 antibodies, and p24 antigen. Serum ACE, soluble Interleukin-2 receptor levels, serum and urine calcium levels, and repeated imaging studies ruled out sarcoidosis. Protein electrophoresis and immunofixation did not show any paraprotein, findings that rule out an association with HIV, sarcoidosis, or monoclonal gammopathy, as described in some patients in the literature [4–7]. MRI revealed symmetric atrophy of ocular muscles and fatty degeneration of pterygoideus medialis and masseter muscles, no signs of edema or contrast enhancement. Thorough neuromuscular transmission studies as well as spinal cord and brain imaging were unremarkable. No other organs were involved. Muscle biopsy of the sternocleidomastoideus revealed numerous rods, which appeared to be O. Wengert A. Meisel Department of Neurology, Charite-Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany

Clinical Reasoning: Pneumocephalus and pneumorrhachis in a 67-year-old man

A 67-year-old man was admitted to the medical intensive care unit at a hospital in eastern Bavaria. The patient presented with back pain, fever (38.7°C, 101.7°F), disorientation regarding time, place, and his own identity, and drowsiness, all of which had developed in recent weeks. Apart from these findings, the neurologic examination was unremarkable. One day before admission, the patient had been placed on an IV broad-spectrum antibiotic regimen of ceftriaxone and combined piperacillin and tazobactam in response to increased infection parameters. In addition to the mans febrile temperature, his leukocyte count was elevated to 12,500/μL; however, examinations of urea, electrolytes, blood sugar, and liver and thyroid functions yielded unremarkable findings. In the absence of a specific focus from the internal medicine perspective, the possibility of meningoencephalitis was considered. A cranial CT study detected diffuse subarachnoid pneumocephalus with generalized accumulation of gas in the cranial cavities (figure 1). There was no recognizable point of entry for the gas.

Fatal Encephalitic Borna Disease Virus 1 in Solid-Organ Transplant Recipients.

Fatal Zoonotic Viral Infection after Transplantation Evidence of Borna disease virus 1 infection in humans is limited; in this report, donor-derived Borna virus encephalitis is shown to occur in three solid-organ transplant recipients.

Perceptions on the value of bodily functions in multiple sclerosis

In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians’ perceptions.

Fulminant Acute Ascending Hemorrhagic Myelitis Treated with Eculizumab

We describe an 18-year-old patient who developed back pain, rapidly ascending sensomotory deficits, bladder dysfunction, Lhermitte’s sign, absent abdominal reflexes of all three levels, brisk tendon reflexes, and positive Babinski’s sign. Magnetic resonance imaging of the spinal cord showed a long segment of cervical and thoracic intramedullary signal hyperintensity suggesting a longitudinally extensive transverse myelitis possibly within the course of a fast progressing ascending immune-mediated hemorrhagic myelopathy. Throughout his illness, the patient deteriorated with tetraplegia, cardiac arrest, and respiratory failure although he received, after exclusion of infective causes, therapy with steroids, immunoglobulins, plasmapheresis, and cyclophosphamide. Interestingly, treatment with the C5-inhibitor eculizumab to prevent complement-mediated spinal cord injury achieved an arrest of clinical deterioration. We propose eculizumab as treatment in fast progressive and potentially fatal immune-mediated spinal cord injury. Furthermore, this case raises awareness for the process of clinical decision-making in severe myelopathies.