[Causes of death in amyotrophic lateral sclerosis : Results from the Rhineland-Palatinate ALS registry]. / Todesursachen bei amyotropher Lateralsklerose : Ergebnisse aus dem ALS-Register Rheinland-Pfalz.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is associated with an increased mortality. Knowledge of possible causes of death could lead to an individualization of the palliative treatment concept and result in a differentiated palliative treatment pathway. Currently, only few systematic data are available on the heterogeneity of causes of death associated with ALS. OBJECTIVE: Analysis of the various causes of death in a prospective population-based German cohort of ALS patients. MATERIAL AND METHODS: Analysis of data of the Rhineland-Palatinate ALS registry in which newly diagnosed patients who had been identified between October 2009 and September 2012 were prospectively enrolled and followed up at regular intervals. From this prospective cohort study the causes of death were elicited based on information provided by the attending physicians, family members and by means of death certificates registered by the regional health authorities in Rhineland-Palatinate. RESULTS: Out of 200 ALS patients registered 148 died between register initiation on 1 October 2009 and the end of follow-up on 30 September 2015 (78 males and 70 females, death rate 74%). The most frequent cause of death was respiratory failure as a consequence of weakness of respiratory muscles (n = 91, 61%). Less frequent causes of death were pneumonia (n = 13, 9%), terminal cachexia (n = 9, 6%) and death from cardiovascular causes including sudden death (n = 9, 6%). Cases of suicide were rare (n = 3, 2%) as were deaths due to concurrent diseases (n = 2). In 21 cases (14%) the exact cause of death could not be clarified. Differences in the causes of death only showed a tendency towards the ALS phenotype. Respiratory failure was the cause of death in all patients with a respiratory phenotype and in 78% of patients with flail arm syndrome. Despite the low number of patients (8%) with additional frontotemporal dementia (FTD) a distinct difference in causes of death between those with and without FTD could be observed. Death due to respiratory failure was less frequent in ALS patients with FTD (33% vs. 65%) while pneumonia was more frequent (27% vs. 7%). CONCLUSION: Respiratory failure was the most frequent cause of death in our cohort of ALS patients. In contrast, pneumonia and nutritional disorders played a less important role as the cause of death. The phenotypic expression of ALS might in part allow the cause of the prospective death to be predicted. Differentiation of ALS phenotypes is an important foundation for patient counseling on the process of dying to be expected and for the determination of an individual palliative concept.

Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

Efficacy of natalizumab in second line therapy of relapsing-remitting multiple sclerosis: results from a multi-center study in German speaking countries.

BACKGROUND: Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population. METHOD: Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab >or=12 months prior to study conduction. RESULTS: Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 +/- 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >or= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>or= 2 relapses in the year and >or= 1 Gadolinium (Gd)+ lesion at study entry, n = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity). CONCLUSION: Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.

Cavernous malformation with hemorrhage of the conus medullaris and progressive sensory loss.

Numerous studies have shown that cavernous malformations may be localized in almost every region of the brain as well as in the spinal cord. Spinal cord cavernous malformations (SCCM) have been diagnosed more frequently since magnetic resonance imaging (MRI) has become more widely available. Most are asymptomatic but may present as a diagnostic challenge with diffuse symptoms ranging from mere sensory deficits to paraparesis possibly affecting both upper and lower motor neuron. A 29-year-old Arabian man was admitted to the hospital with a progressive sensory loss to light touch, pin prick and vibration of the right and in a lesser extent of the left leg without any association to a particular dermatome. He additionally presented with progressing paresthesias in both legs, unsteady gait and incipient bladder- and bowl incontinence starting approximately 1 week prior to admission. Spinal MRI showed a central, slightly lateralized intramedullary lesion 1 cm in diameter located within the conus medullaris that was suspicious for an intramedullary cavernous malformation. The lesion was accompanied by a perifocal edema and showed an inhomogeneous hypointense core on T2WI consistent with an acute cavernous hemorrhage. Treatment of symptomatic intramedullary cavernous angiomas should, if possible, consist of total surgical excision. It is essential to achieve complete removal during the first operation to avoid any residues that may lead to further bleeding.

Evolution of purely infratentorial PML under HAART--negative outcome under rapid immune reconstitution.

Progressive multifocal leukoencephalopathy (PML) caused by the polyomavirus JC is a well-recognised complication of AIDS. Purely infratentorial manifestations are rare. Introduction of highly active antiretroviral therapy (HAART) has been associated with a reduction in morbidity and an improvement in overall survival among HIV-infected individuals. Recently, several reports have described adverse events in patients with PML who begin HAART and show evidence for immune reconstitution. We describe the clinical course of two patients with PML with purely infratentorial manifestation, whose clinical course deteriorated despite the successful introduction of HAART. Possible underlying immunological mechanisms are discussed.

Basal ganglia infarction mimicking glioblastoma.

Modern brain imaging techniques usually allow a very good differential diagnosis of intracerebral lesions, but in some cases the differential diagnosis is difficult. We report the case of a 52 year old male with acute brachiofacial paresis and a hyperintense lesion with mass effect and ring-enhancement in basal ganglia suspiciously to a tumor. The neurosurgeons recommend stereotactical brain biopsy for diagnosis, but the patient recovered in following time gradually and in repeated computer tomographic images contrast enhancement disappeared and a hypodense zone in the basal ganglia remains. Our case demonstrates that brain infarctions can mimick glioblastoma in taking cystic appearance and contrast enhancement. Stereotactic biopsy would have been a precipitated invasive procedure in this case.

Children and adolescents with chronic cerebellar lesions show no clinically relevant signs of aphasia or neglect.

We studied language and visuospatial functions of 12 children and adolescents who had undergone surgery for cerebellar astrocytoma without subsequent radiation or chemotherapy and compared them with 27 age-, gender-, and education-matched healthy control subjects. To study possible lateralization of the functions of the left and right cerebellar hemispheres, subjects performed several language tasks including a verb-generation task as well as standard neglect and extinction tests. Three-dimensional-MR images confirmed that lesions affected cerebellar hemispheres in all children but one who had a pure vermal lesion. The right cerebellar hemisphere was affected in six, the left hemisphere in four children, and both hemispheres in one child. There were no signs of aphasia in the children or adolescents with cerebellar lesions. Language abilities did not differ between cerebellar patients and control subjects except for small increases in reaction times in verb generation in patients with left-sided lesions. Visuospatial functions were also intact in cerebellar subjects except for minor group differences in neglect tasks. In sum, chronic focal cerebellar lesions acquired in childhood or youth do not result in persistent language disorders or clinically significant signs of spatial neglect or extinction.

Comparison of eyeblink conditioning in patients with superior and posterior inferior cerebellar lesions.

The aim of the present study was to compare eyeblink conditioning in cerebellar patients with lesions including the territory of the superior cerebellar artery (SCA) and in patients with lesions restricted to the territory of the posterior inferior cerebellar artery (PICA). The cerebellar areas known to be most critical in eyeblink conditioning based on animal data (i.e. Larsell lobule H VI and interposed nucleus) are commonly supplied by the SCA. Eyeblink conditioning was expected to be impaired in SCA, but not in PICA patients. A total of 27 cerebellar patients and 25 age-matched controls were tested. Cerebellar lesions were primarily unilateral (n = 20). Most patients suffered from ischaemic infarctions of the SCA (n = 11) or the PICA (n = 13). The other patients presented with cerebellar tumours (n = 2) and cerebellar agenesis (n = 1). The extent of the cortical lesion (i.e. which lobuli were affected) and possible involvement of the cerebellar nuclei was determined by 3D-MRI. As expected, the ability to acquire classically conditioned eyeblink responses was significantly reduced in the group of all cerebellar patients compared with the controls. In the patients with unilateral cerebellar lesions, conditioning deficits were present ipsilaterally. In SCA patients with lesions including hemispheral lobules VI and Crus I, eyeblink conditioning was significantly reduced on the affected side compared with the unaffected side. No significant difference between the affected and unaffected sides was present in patients with lesions restricted to the common PICA territory (i.e. Crus II and below). Conditioning deficits were neither significantly different in SCA patients with pure cortical lesions compared with SCA patients with additional nuclear impairment nor in SCA patients with unilateral lesions compared with SCA patients with bilateral lesions. To summarize, unilateral cortical lesions of the superior cerebellum appear to be sufficient to reduce eyeblink conditioning in humans significantly.

Posterior reversible encephalopathy syndrome due to severe hypercalcemia.

Posterior reversible encephalopathy syndrome (PRES) is a leukoencephalopathy clinically characterized by headache, altered mental status, visual loss and seizures. Neuroimaging demonstrates symmetrical posterior cortical and subcortical lesions. The exact pathophysiology is unknown but there is a strong association with immunosuppressants and hypertension. We report two cases of PRES in normotensive patients with severe hypercalcemia as the only identifiable cause. Possible pathophysiological mechanisms are discussed.

Progressive multifocal leukoencephalopathy limited to the brain stem.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating slow-virus encephalitis caused by the JC polyomavirus in 2-5% of patients with AIDS. MRI typically shows multiple lesions in the cerebral hemispheres. We present a rare case of rapidly evolving and lethal PML with a severe bulbar syndrome and spastic tetraparesis in a patient with AIDS. MRI showed high-signal lesions on T2-weighted images confined to the brain stem, extending from the medulla oblongata to the midbrain. JC virus polymerase chain reaction in cerebrospinal fluid was positive, and neuropathology showed the findings of PML. This case was also notable because of the rapid progression despite improved immune status with antiretroviral therapy.

Is stereotactic biopsy a reliable method to differentiate tumor from radiation necrosis?

We report a case of a 37-year-old female who suffered from seizures and underwent external beam radiotherapy due to a suspected low-grade astrocytoma in the left hemisphere. After 7 years free of seizures under antiepileptic treatment and no signs of change in the yearly performed control MRI, she developed a progressive right-sided hemiparesis. MRI now showed an enhancing lesion with space occupying perifocal edema in the entire left hemisphere. Stereotactic biopsy revealed only inflammation. Due to further progress of the neurological deficit an open biopsy was performed. Histological examination revealed a middle-graded astrocytoma and a radiation necrosis. This case demonstrates that radiation necrosis and tumor recurrence may develop concurrently and that it may be difficult to distinguish them by clinical or radiological methods.

Fear conditioned changes of heart rate in patients with medial cerebellar lesions.

Fear conditioned changes of heart rate and skin conductance responses were investigated in patients with medial cerebellar lesions. A classical conditioning paradigm with a tone as the conditioned stimulus (CS) and an electrical shock as the unconditioned stimulus (US) was tested on five patients with medial cerebellar lesions due to surgery for astrocytoma and five controls. The CS preceded the US by 5900 ms and coterminated with the US. Changes in heart rate and skin conductance responses were obtained as measures for autonomic fear responses. Effects of conditioning were quantified by comparison of the habituation and extinction phases. Controls, but not cerebellar patients, showed a significant decrease of heart rate during fear conditioning. However, there were no significant fear conditioned changes in electrodermal responses in either group. In summary, the medial cerebellum seems to be involved in fear-conditioned bradycardia in humans.

Cerebral aspergillosis: comparison of radiological and neuropathologic findings in patients with bone marrow transplantation.

Thirty-six lesions in six patients who died from cerebral Aspergillus infection after bone marrow transplantation (BMT) were studied with regard to signal intensity, contrast enhancement, size, and location. The diagnosis was confirmed in all cases by autopsy. Retrospective correlation of histopathological and radiological findings was possible for 14 lesions. Most of the lesions (22/36) had isointense to low signal intensity on T2-weighted images (T2WI). Histopathologically, hemorrhagic necrosis was determined in three of them. Areas of high signal intensity on T1-weighted images (T1WI) were related to gross hemorrhage. Two infarctions showed intravascular accumulation of fungal hyphae with secondary thrombosis of the vessel. The remaining 12 lesions had high signal intensity on T2WI and low on T1WI. Histopathologically, four were infectious and four were unspecific demyelinated lesions. In conclusion, cerebral aspergillosis typically presented with large lesions showing isointense to low signal intensity on T2WI that could have areas of high signal on T1WI. Contrast enhancement was only visible in 15 lesions, and the predominant locations were the subcortical white matter, the cerebellum, and the basal ganglia. Small lesions with high signal on T2WI and low signal on T1WI could not necessarily be related to Aspergillus infection.

Involvement of the human medial cerebellum in long-term habituation of the acoustic startle response.

Animal studies have shown an involvement of the cerebellar vermis in long-term habituation of the acoustic startle response, but not in short-term habituation. The aim of the present study was to investigate whether short-term and long-term habituation of the acoustic startle response are impaired in patients with medial cerebellar lesions. Five patients with midline cerebellar lesions due to surgery for astrocytoma and ten healthy, age- and sex-matched subjects were studied. Subjects received 40 acoustic startle stimuli each day on five successive days. Peak amplitudes of the startle response recorded at the orbicularis oculi and the sternomastoid muscles were obtained. Data were analyzed for response decrement within the training session of one day (short-term habituation) and for a decrease in the startle response across the five training days (long-term habituation). Short- and long-term habituation of the startle response recorded at the sternomastoid muscles could be achieved in controls and in cerebellar patients. However, long-term habituation of the blink component of the acoustic startle response recorded at the orbicularis oculi muscles was significantly impaired in patients with cerebellar lesions compared with control subjects, whereas short-term habituation was preserved in both groups. The present findings suggest that the medial cerebellum is involved in long-term habituation of the blink component of the startle response in humans.

MRI of intracranial toxoplasmosis after bone marrow transplantation.

Toxoplasma encephalitis was confirmed by biopsy in three patients with bone marrow (BMT) or peripheral blood stem-cell transplantation (PBSCT). All had MRI before antimicrobial therapy. The intensity of contrast enhancement was very variable. One patient had one large, moderately enhancing cerebral lesion and several smaller almost nonenhancing lesions. The second had small nodular and haemorrhagic lesions without any enhancement. The third had late cerebral toxoplasmosis and showed multiple lesions with marked contrast enhancement. The moderate or absent contrast enhancement in the two patients in the early phase of cerebral toxoplasmosis may be related to a poor immunological response, with a low white blood cell count in at least one patient. Both received higher doses of prednisone than the patient with late infection, leading to a reduced inflammatory response. In patients with a low leukocyte count and/or high doses of immunosuppressive therapy, typical contrast enhancement may be absent.

Opportunistic CNS infection after bone marrow transplantation.

We retrospectively identified opportunistic CNS infections in 655 patients who had undergone allogeneic, syngeneic or autologous BMT or PBSCT between 1990 and 1997. Twenty-seven patients (4%) developed CNS infections. All CNS infections occurred in allogeneic BMT or PBSCT patients. The most common CNS infections were toxoplasma encephalitis (74%) and cerebral aspergillosis (18%). Furthermore, we identified one patient with candida encephalitis and one patient with viral encephalitis. Overall mortality of patients with opportunistic CNS infection was 67%. There were two different groups of toxoplasma encephalitis with a different appearance on MR imaging. The first group showed edema, but no gadolinium enhancement, whereas the second group exhibited typical MRI appearances with the exception of frequent hemorrhagic transformation. The first group had a significant shorter latency between BMT and onset of CNS infection (mean 45 days vs 180 days, P = 0.02), a significant higher daily dose of corticosteroids as treatment for graft-versus-host disease (GVHD) (P = 0.01), more severe GVHD and a higher mortality (71% vs 36%). This study shows that the most common CNS infections in our patient population are toxoplasma encephalitis and cerebral aspergillosis, that there are two distinct subgroups of toxoplasma encephalitis and that CNS infections occur after allogeneic BMT only.

Multiple intracerebral metastases of a 17-year-old girl with previously diagnosed neurofibromatosis type I.

We report a case of a 17-year-old girl with multiple intracerebral tumors. Previously, a neurofibroma in the posterior mediastinum and neurofibromatosis had been diagnosed. She developed a spastic tetraparesis with a prominent hemiparesis of the right side within several weeks. On admission we found clinical signs of elevated intracranial pressure. Cranial CT and MRI scans showed multiple space-occupying intracerebral tumors, thought to be multiple meningeoma. The patient was referred to the neurosurgical department, where two of the intracerebral tumors were excised. The histological examination revealed metastases of a neurosarcoma.

Are allergic reactions to skin clips associated with delayed wound healing?

BACKGROUND: Metal skin clips are used in surgery. They may contain metals that might cause allergic reactions and delayed wound healing. METHODS: The metal composition of 18 different surgical clamps was examined. The allergy status of 184 patients was determined by patch tests and was correlated with the clinical outcome of wound healing after application of skin clips. RESULTS: Skin clips contained chromium, nickel, molybdenum, cobalt, and titanium in concentrations high enough to cause allergic reactions. Eighteen percent of the men and 23% of the women were sensitive to nickel and 16% of the men to chromium. We found a positive correlation between the grade of nickel allergy and the reaction to the skin clips. CONCLUSIONS: Our study suggests that allergic reactions and delayed wound healing can be caused by the use of surgical skin clips. Therefore skin clips are not recommended for patients with a history of contact dermatitis to metals and/or atopy.