Heinz Lahrmann

P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy

SummaryThe co-administration of antiepileptic drugs (AED) and chemotherapeutic agents in patients with glioblastoma multiforme (GBM) is common. Interactions of chemotherapeutic agents and AED have not been investigated sufficiently. The purpose of this study is to evaluate the effects of enzyme inducing (EI-AED) and non-EI-AED in patients with GBM treated with standard chemotherapeutic agents on survival and haematotoxicity. One hundred and sixty eight glioblastoma patients with standard treatment including surgery, radiotherapy and chemotherapy were retrospectively analysed. Patients were separated into three groups: Group A patients without AED (n=88), Group B patients with EI-AED (n=43), and Group C patients with non-EI-AED (n=37). CCNU was the most frequently used first-line drug in all three groups (Group A: 77%; Group B: 81%; Group C: 78%). Second line treatment, mainly temozolomide, was applicated in 58 of patients and third-line treatment in 9. Carbamazepine was the most frequently administered AED in Group B (81%) and valproic acid in Group C (85%). For statistical analysis, only patients with CCNU first line treatment were calculated. A significant difference regarding survival was detected between Group B (10.8 month) and Group C (13.9 month), as well as increased haematotoxicity for Group C. These results indicate that AED influence the pharmacokinetics of chemotherapeutic drugs in patients with GBM. Valproic acid might be responsible for increasing haematotoxicity. Whether the difference regarding survival between Group B and Group C is due to a decrease of efficacy of chemotherapeutic agents by EI-AED, or due to increased efficacy of chemotherapeutic agents caused by the enzyme inhibiting properties of valproic acid, has to be evaluated in future studies.

Neuralgic amyotrophy with phrenic nerve involvement

Phrenic nerve involvement is a rare feature in patients with neuralgic amyotrophy (Parsonage–Turner syndrome). We report four patients who initially presented with severe dyspnea in the absence of lung disease. All patients had a history of infectious disease or surgery and of pain of sudden onset in the shoulder region. Weakness of the proximal arm was observed in only one. Radiographic and pulmonary function studies, phrenic nerve conduction studies, and needle electromyogram (EMG) of the diaphragm documented diaphragmatic paralysis which was unilateral in one patient, bilateral in two patients, and recurrent on alternating sides in another one. Follow‐up studies remained abnormal for up to 4 years. Neuralgic amyotrophy with phrenic nerve involvement should be considered in patients presenting with severe, unexplained dyspnea of sudden onset.

The End-of-Life Hospital Setting in Patients with Glioblastoma

Despite aggressive treatment, outcome of patients with glioblastoma is poor. Several distinct clinical problems arise in the terminal stage of this disease. The purpose of this study was to evaluate the end-of-life phase in a hospital setting in patients with glioblastoma. Twenty-nine consecutive patients with glioblastoma, who died in our department, were included in this analysis regarding symptoms, medication, diagnostics, and interventional procedures. The patients were comparable with respect to age, gender, and overall survival with data from the literature. Relevant clinical symptoms, medications, diagnostics, well as interventional procedures increased continuously toward end of life. Pain, epileptic seizures, and symptoms of brain edema were the most frequent clinical symptoms. According to this, most patients were on antiepileptic drugs (AED), steroids, and analgesics. In the last phase, symptoms from brain edema, fever, decrease of vigilance, dysphagia, and pneumonia were the prominent clinical features. Our study demonstrates that the end of life in patients with glioblastoma has several periods with different clinical aspects with respect to symptoms and treatment.

Acquired neuromyotonia and peripheral neuropathy in a patient with Hodgkin's disease.

Acquired neuromyotonia is characterized by hyperexcitability of motor nerves resulting in continuous muscle fiber activity. It occurs most often as a paraneoplastic syndrome in patients with cancers of the immune system. Antibodies against voltage‐gated potassium channels (VGKCs) have been detected in some patients. Peripheral neuropathy is sometimes present. We report on a patient with Hodgkins lymphoma in complete remission who developed paresthesias followed by neuromyotonia with bulbar involvement. Peripheral sensorimotor neuropathy was diagnosed electrophysiologically and evidence of axonal degeneration and demyelination was detected by sural nerve biopsy. The patients complaints, including dysarthria, improved after carbamazepine treatment.

No Effect of Naloxone on Ventilatory Response to Progressive Hypercapnia in IDDM Patients

The ventilatory response to hyperoxic progressive hypercapnia was examined by comparing 3 test groups: 7 diabetic patients with AN, 8 diabetic patients without AN, and 8 normal control subjects. In each group, a significant linear correlation was found between PaCO2 and VE. The slopes of the regression curves relating PaCO2 to VE were significantly steeper in the healthy control subjects and diabetic patients without AN than in those with AN (P < 0.01). We conclude that the ventilatory response to progressive hypercapnia is reduced in diabetic patients with AN. By analyzing the power spectrum and the amplitude behavior of the diaphragmatic EMG (calculated from the fc and RMS, respectively), we could exclude a disturbance of neural descending pathways and respiratory muscle dysfunction as possible causal mechanisms for the impaired ventilatory response to increasing CO2. By using lung function analysis, causal factors such as alterations in respiratory system mechanics also could be excluded. As diabetes is known to affect the endogenous opioid system, which, in turn, affects the ventilatory response to CO2, naloxone, as a specific opioid antagonist, was administered in all 3 test groups. Naloxone produced a significant increase of ventilatory response to hypercapnia in the healthy control subjects (P < 0.01), but produced no effect in either of the diabetic groups. We conclude that the ventilatory response to hypercapnia is impaired in diabetic patients with AN, that lung function alterations and diaphragmatic muscle dysfunction are not responsible for this impairment, and that endogenous opioids produce an effect on the response to CO2 in healthy subjects, but they have no effect on CO2 response in diabetic patients with or without AN. These results suggest that the central control of respiration is pathologically altered in diabetic patients with AN.

Expiratory muscle weakness and assisted cough in ALS

Elimination of airway secretion is a major issue in the care of patients with ALS. Sufficient cough flows have to be generated by expiratory muscles to allow airway clearance. Bulbar and expiratory muscle weakness are often reasons for failure of non‐invasive ventilation (NIV) and may lead to tracheostomy. Expiratory aids may help to overcome these problems, at least for some time. We report a patient with advanced ALS, receiving nocturnal NIV, who gained much benefit from regular use of a mechanical in‐exsufflation device.

Familial Creutzfeldt-Jakob disease initially presenting with alien hand syndrome

Sirs: Alien hand syndrome (AHS) is described as a combination of involuntary hand movements with a sense of alienness or estrangement of the affected hand. It has been reported in stroke [1], in subarachnoid hemorrhage, neoplasm, corticobasal degeneration [2], trauma, in Alzheimer’s disease[3], and in sporadic Creutzfeldt-Jakob disease (CJD) [4–5]. In patients with AHS, the most frequent pathological findings are focal lesions to the anterior corpus callosum (non dominant AHS) or a combination of callosal and frontal lesions (frontal AHS) [4, 6]. Although the range of signs and symptoms of the familial CJD, representing 5 to 10 percent of all cases, is very similar to that of the sporadic form, AHS so far has never been described in familial CJD. We report a patient who initially presented with AHS, without classic symptoms of CJD such as ataxia, dementia, and startle myoclonus. This familial case of CJD adds to the previous reports of alien hand syndrome in sporadic CJD. A 74 year old female, right handed patient, without relevant medical history presented with a two week history of clumsiness and weakness in her left hand. She described a strange feeling, as if her left hand did not belong to her, and took part in progressive involuntarily initiated complex movements. Initially a stroke, as a possible cause, had been suggested by the referring neurologist. On neurological examination she was fully alert, orientated, and cooperative. Bedside neuropsychological evaluation revealed no overt cognitive symptoms. The MiniMental-Test, scored 28 and was considered normal. She had a mild distal paresis and ataxia in the left hand as well as a positive grasp reflex. Spontaneous involuntary athetoid like movements of the left hand (see figure), as well as impairment of bimanual motor control were noted. No sensory loss could be detected. Deep tendon reflexes of the upper and lower limbs were symmetrically brisk. The autonomous complex movements and impaired bimanual control of the left hand together with difficulty in recognizing the hand, gave the picture of AHS. Within 3 months she developed rapidly progressive dementia and generalized myoclonus. Finally she was bedridden. Occasional tonic seizures occurred, as well as progressive swallowing difficulty. She exhibited increased startle reaction, and plantar reflexes were extensor. The patient died 3 months after onset of the disease from cardiopulmonal failure. Family history revealed a brother who had died in 1994 because of neuropathologically confirmed CJD. Routine blood samples were normal. MRI investigations showed multiple periventricular subcortical localized confluent T2 weighted hyperintense lesions suggesting a vascular origin. CSF analysis revealed normal protein and cell count, levels of Tau-protein were increased (1090 pg/ml) and assay for the 14-3-3 protein was positive. EEG studies demonstrated multilocular periodic triphasic elements. Electrophysiological examination showed normal nerve conduction velocities, while electromyography exhibited discharges, that were interpreted as pseudomyotonic in the abductor dig. V and interosseus I muscle on the left hand, and may have been retrospectively a sign of a startle reaction. Electromyography of the right deltoideus muscle was normal. Postmortem neuropathological examination showed diffuse spongiform encephalopathy. ParafLETTER TO THE EDITORS

Trigeminal Neuralgia in Two Patients With Glioblastoma

Headache in glioblastoma patients often indicates raised intracranial pressure by either tumor edema or tumor progression. We report local glioblastoma growth causing cranial nerve lesions as well as trigeminal neuralgia, and highlight pain management in these patients.

Diagnosing Autonomic Nervous System Disorders - Existing Guidelines and Future Perspectives

Primary and secondary autonomic nervous system (ANS) disorders often have a severe adverse effect on the quality of life of patients. Diagnostics for ANS disorders are under represented, despite their common occurrence. Precise history taking is of key importance for ANS evaluation: it may help to rule out differential diagnoses and provide important clues to the underlying ANS disorder. In fact, in conjunction with additional bedside tests, it can achieve a clear diagnosis. The analysis of heart rate variability and the results of the standardised tests that make up the Ewing battery are important means of evaluating the parasympathetic and sympathetic nervous system. In addition, sudomotor testing can be used to evaluate cholinergic sympathetic function, and the spontaneous baroreceptor reflex can be assessed using new computerised techniques. These tests provide valuable information on cardiovascular autonomic control. This paper presents a structured review of current standard techniques for diagnosing ANS disorders.

Inspiratory muscle performance relative to the ventilatory threshold in healthy subjects.

Inspiratory muscle performance, ventilation, and gas exchange were studied during exercise in healthy subjects to look for typical changes of pattern of contraction at the ventilatory threshold (VT). The steepening of the slope of carbon dioxide output (VCO2) vs oxygen uptake (VO2) at the VT was accompanied by a nonlinear increase of the mean rate of esophageal pressure development (Pes/TI) vs the esophageal pressure time index (PTIes) reflecting both the relative force (Pbreath/Pesmax) and duration (TI/TTOT) required for inspiration. The esophageal pressure time integral within one breath (Pbreath.dTI) was one of the best single predictors of the ventilatory equivalent for oxygen (VE/VO2) at the VT. Moreover, we presented inspiratory muscle load indices as a mirror image of breathing pattern, with the obvious advantage that the ventilation component can be compared with better established methods of presenting ventilatory output. Inspiratory muscle performance during exercise should link the increased metabolic rate to ventilatory output. We conclude that 1) there exists an inspiratory muscle threshold that is well correlated to commonly used gas exchange thresholds, and 2) the efficiency of ventilation and gas exchange during exercise could be linked to pressure and timing of inspiratory muscle contraction.