Prevalence of narcolepsy with cataplexy in Norway.

OBJECTIVES: Narcolepsy is a lifelong disabling disorder that may be alleviated by relevant treatment. Patients frequently report 10-15 years from the first symptoms to the time they get the diagnosis and treatment can be started. In order to offer a sufficient diagnostic and therapeutic service to this patient group, a reliable estimation of the prevalence of the disorder is important. A study of the prevalence of narcolepsy with cataplexy in Norway was therefore undertaken. MATERIALS AND METHODS: The Ullanlinna Narcolepsy scale (UNS) was sent to 14548 randomly selected Norwegians between 20 and 60 years. Additionally, the study included telephone interviews and clinical evaluation of responders with >or=14 points on the UNS, and in those with suspected narcolepsy, polygraphic sleep recordings and human leucocyte antigen (HLA)-typing. RESULTS: A total of 8992 responders answered the questionnaire (response rate 61.8%), 267 had >or=14 points on the UNS, 156 were interviewed and 15 had sleep recordings. In two HLADQB1*0602-positive patients sleep recordings were compatible with narcolepsy. CONCLUSIONS: The results indicate a prevalence of 0.022% and approximately 1000 patients with narcolepsy with cataplexy in Norway.

Effect of the fluoropyrimidines 5-fluorouracil and doxifluridine on cellular uptake of thiamin.

The effect of 5-fluorouracil (5-FU) and doxifluridine on cellular uptake and phosphorylation of thiamin was studied in two different cell systems. Uptake of 14C-Thiamine in human NHIK 3025 cells preincubated for 24 h with 0.05 mM 5-FU or 0.1 mM doxifluridine was increased by 22-26% relative to nontreated control cells. In isolated rat hepatocytes a drug-induced increase in thiamin uptake by 40-45% was found following 2 h incubation both with 5-FU and doxifluridine. High performance liquid chromatography (HPLC) showed an increase in intracellular thiamin diphosphate (TPP), while free thiamin (T) remained unchanged in drug-exposed cells, indicating an increased phosphorylation of thiamin. The results indicate that fluoropyrimidines may increase the cellular thiamin metabolism, possibly resulting in clinical symptoms of thiamin deficiency if the dietary intake is not increased correspondingly.

Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy.

BACKGROUND: The association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75-90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy. METHODS: Two patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aß42), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF. RESULTS: The concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups. CONCLUSION: The findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.

Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A.

BACKGROUND: From October 2009 to January 2010, approximately 470,000 children and adolescents in Norway ages 4-19 years were vaccinated with Pandemrix® against influenza A (H1N1 subtype). The vaccination coverage in this age cohort was approximately 50%. OBJECTIVES: Our study was performed to evaluate the possible association between Pandemrix® vaccination and narcolepsy in Norway. METHODS: Children and adolescents with sudden onset of excessive daytime sleepiness (EDS) and cataplexy occurring after the 2009-2010 vaccination period were registered by the National Institute of Public Health in cooperation with the Norwegian Resource Center for AD/HD, Tourette Syndrome, and Narcolepsy. RESULTS: Fifty-eight vaccinated children and adolescents (35 girls, 23 boys) ages 4-19 years (mean age, 10.5 years) were diagnosed as new cases of confirmed narcolepsy and were included in our study during 2010 and 2011. Forty-two children had onset of symptoms within 6 months after vaccination, with 12 of them having symptoms within the first 6 weeks. All had EDS, 46 had documented cataplexy, 47 had mean sleep latency less than 8 min, and 43 had two or more sleep-onset rapid eye movement sleep (SOREM) periods in multiple sleep latency tests (MSLT). Cerebrospinal fluid (CSF) hypocretin levels were measured in 41 patients, with low levels in all. Thirty seven patients that were analyzed had tissue type HLADQB1*0602. During the same period, 10 unvaccinated cases were reported (mean age, 12.5 years). CONCLUSION: The data collected during 3 years following vaccination showed a significantly increased risk for narcolepsy with cataplexy (P<.0001) and reduced CSF hypocretin levels in vaccinated children ages 4-19 years the first year after Pandemrix® vaccination, with a minimum incidence of 10 of 100,000 individuals per year. The second year after vaccination, the incidence was 1.1 of 100,000 individuals per year, which was not significantly different from the incidence of 0.5-1 of 100,000 per year in unvaccinated children during the same period.

Health-related quality of life in narcolepsy.

OBJECTIVES: To describe health-related quality of life in Norwegian patients with narcolepsy compared with data from the general population. PATIENTS AND METHODS: Seventy-seven patients with narcolepsy with cataplexy were included in the final analysis. Health-related quality of life was assessed by SF-36 questionnaire. RESULTS: Men and women with narcolepsy had lower scores in all SF-36 domains, except vitality. Most profoundly affected were bodily pain (men: p = 0.0001, women: p = 0.0001), social function (men: p = 0.0001, women: p = 0.0001) and general health (men p = 0.04, women: p = 0.0001). CONCLUSIONS: Narcolepsy has a clear negative effect on quality of life which is not sufficiently counteracted by medical treatment. We suggest that earlier diagnosis and treatment after onset of symptoms may be important in reducing the negative effects on quality of life. Special attention should be paid to the patients social functioning and general well-being.

[Narcolepsy in children--a diagnostic and therapeutic challenge]. / Narkolepsi hos barn--en diagnostisk og terapeutisk utfordring.

Narcolepsy is a socially and psychologically disabling disease that most often develops in adolescence or early adulthood. In a number of studies about one-third of the patients had experienced the first symptoms before the age of 15. The diagnosis and subsequent treatment is usually not established until several years later, often ten to fifteen years after the appearance of the first symptoms. If unrecognized and untreated, narcolepsy may lead to serious psychological and social problems during childhood and early adulthood, which may in turn cause difficulties in social adjustment later in life. This stresses the importance of early diagnosis. The diagnosis is based on clinical and polysomnographic criteria. In children, however, the clinical symptoms and polysomnographic findings may be atypical, making it difficult to establish a definite diagnosis. Three patients, two five-year olds and one four and a half-year old, are presented to illustrate the problems and considerations which must be taken into account in the diagnosis and treatment of children with narcolepsy.

Wernicke-Korsakoff-like syndrome in patients with colorectal carcinoma treated with high-dose doxifluridine (5'-dFUrd).

5'-dFUrd (doxifluridine) is a new fluoropyrimidine that may have a higher antitumor effect and less side effects than 5-FU. In this study 15 patients with advanced colorectal carcinoma, one with renal carcinoma, one with carcinoid and one with advanced carcinoma of unknown origin, were randomly assigned to receive 5'-dFUrd 5 g/m2 or 3 g/m2 as a 1-h infusion for 5 days in 3 cycles at intervals of 4 weeks. The patients had repeated neurological and neurophysiological examinations before and during the treatment. Ten patients developed symptoms of toxicity of the central nervous system (CNS), with cerebellopathy and encephalopathy resembling a Wernicke-Korsakoff syndrome. The neurotoxicity was dose related, affecting 7 of 8 patients in the high dosage group and 3 of 9 patients in the low dosage group. The symptoms generally started at the end of the second week of the cycle with unsteadiness and diplopia, and progressed to the fourth week with ataxia, confusion and EEG-changes, becoming more pronounced with increasing number of cycles. After the treatment there was normalisation within 4-8 weeks. Cachectic patients and patients with a pathological EEG before treatment seem to represent a high-risk group for CNS-symptoms. EEG may be helpful in early diagnosis of CNS-toxicity.

Neurological manifestations in a phase 2 study of 13 patients treated with doxyfluridine.

Doxyfluridine is a new cytostatic drug of the fluoropyrimidine group, which may prove to have a high antitumor activity with less toxic side effects. Thirteen patients with advanced colorectal cancer were given doxyfluridine 2 g/m2 as a one-hour infusion for five days every three weeks and examined neurologically and neurophysiologically. One patient experienced an acute, reversible cerebellopathy after the second treatment course and developed a progressive generalized encephalopathy during the subsequent third and fourth cycle. The frequency of cerebellopathy may depend on the dosage and type of administration of the drug. Five patients developed a mild, mainly sensory polyneuropathy. High age, weight loss and decreasing general condition seem to be important factors in the development of polyneuropathy during doxyfluridine treatment, and this stresses the importance of optimal nutrition during the treatment period.

Passage of 5'-dFUrd and its metabolites 5-FU and 5-FUH2 to CSF in a clinical phase 1 study.

Lumbar puncture was performed on eight patients in a clinical Phase 1 study of doxifluridine (5'-dFDrd). 5'-dFUrd, 5'FU, and 5-FUH2 were shown to cross the blood-brain barrier to CSF. The maximal concentrations of 5'-dFUrd and 5-FUH2 were about 1-3% of the maximal concentrations in plasma, and were reached within 1-4 h after the end of iv infusion of 5'-dFUrd. 5-FUH2 showed a marked increase in CSF between 3 and 4 h to about 40-60% of the maximal plasma concentration in 5 of the patients, indicating a possible further increase after 4 h. The relationship between the concentrations of 5'-dFUrd and its metabolites in the CSF, and CNS toxicity is discussed.

[Treatment of writer's cramp with botulinum toxin]. / Behandling av skrivekrampe med botulinumtoksin.

Writer's cramp is a focal dystonia that is resistant to most treatment regimens. This article describes two patients with writer's cramp who were successfully treated with botulinum toxin injections into the forearm muscles. Transient weakness due to the effect of botulinum toxin was registered in the injected muscles. No other side effects were observed. The beneficial effect of a single injection lasted from three to four months and could be reproduced by repeated injections over a three year follow-up period. We conclude that botulinum toxin injections may provide safe and effective treatment in selected patients with writer's cramp.

Reduced hippocampal field potentials during administration of fluoropyrimidines in vitro.

Toxic effects on the central nervous system have been reported in patients treated with fluoropyrimidines for cancer. In the present study we have investigated the earliest effects of these drugs at the cellular level using slices of hippocampal cortex maintained in vitro. Doxyfluridine (5'-dFUrd; 50 mg/l and 500 mg/l) caused a dose dependent, reversible depression of neuronal activity. The main effect was on the pyramidal cells (population spike reduced by 14 and 25% respectively) and the afferent unmyelinated fibres (afferent fibre volley reduced by 7 and 12% respectively). Excitatory synaptic transmission was affected only by the highest concentration (field-EPSP reduced by 10%). 5-FU caused similar but less marked changes. The drugs did not cause epileptiform activity.

Cranial nerve dysfunction in metastatic cancer of the prostate.

We report 11 patients with cranial nerve dysfunction due to bone metastases from advanced prostatic cancer. Diplopia, speech disturbances, tongue deviation and headache were the typical clinical symptoms. X-ray and/or computed tomography of the base of the skull demonstrated bone destruction (and the surrounding soft tissue tumour) in 8 cases. In 1 patient the bone destruction was visualised only by bone scan. In 2 cases no bone destruction could be demonstrated in spite of the clinical findings. In 9 of the 10 evaluable patients the clinical symptoms improved after high voltage radiotherapy and high dose corticosteroid treatment. Cranial nerve dysfunction is a late complication of hormone-resistant prostatic cancer. The symptoms are usually due to bone destruction at the base of the skull. Radiotherapy combined with corticosteroid treatment is an excellent palliative measure if started immediately after the onset of symptoms.

Azepexole, a potent alpha 2-agonist with anaesthetic effects, does not affect cerebral energy consumption in dogs given isoflurane.

The effects of the alpha 2-agonist azepexole on the cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were studied by a sagittal sinus outflow technique in dogs. Azepexole, 1 mg kg-1 (reported to decrease the anaesthetic requirement for isoflurane by almost 90%), caused no change in CMRO2 when given during 1.4% isoflurane anaesthesia. CBF was reduced by 26%. When the concentration of isoflurane was reduced to 0.2%, CMRO2 increased by 26% as would have been expected for the change in isoflurane concentration alone. Concomitantly CBF increased to a level not significantly different from control. Azepexole might be a useful adjunct to inhalational anaesthetics, and combined with a low dose of isoflurane it should be an excellent background anaesthetic when studying the effect of other drugs on CMRO2 in dogs as the combination seems to have little effect on the CMRO2.

Long-term somatic side-effects and morbidity in testicular cancer patients.

In order to evaluate long-term somatic morbidity after treatment for testicular cancer 149 patients with NED greater than or equal to 3 years answered a questionnaire. The patients had been treated with surgery only (32 patients, radiotherapy only (39 patients), cisplatin-based chemotherapy plus surgery (46 patients) or chemotherapy plus radiotherapy with or without surgery (32 patients). Raynaud-like phenomena were the most frequent side-effect occurring significantly more often after cisplatin-based chemotherapy than after surgery or radiotherapy (33/72 patients versus 5/68 patients). Peripheral sensory 'neuropathy' was reported by 18% of all the patients. Seventeen per cent and 11% complained of pulmonary symptoms and auditory symptoms, respectively. Gastrointestinal side-effects were more frequent after any type of cytotoxic therapy than after surgery only (34/47 patients versus 5/22 patients). Twenty-six patients had fathered children after treatment. About 80% of the patients were in full time wage-earning activity when they answered the questionnaire. In conclusion, 3-7 years after treatment for testicular cancer, 30-50% of the patients had minor somatic complaints whereas serious side-effects seldom occurred.

Effect of dexmedetomidine, a selective and potent alpha 2-agonist, on cerebral blood flow and oxygen consumption during halothane anesthesia in dogs.

The effect of the alpha 2-agonist dexmedetomidine on the cerebral blood flow (CBF) and the metabolic rate for oxygen was studied by a sagittal sinus outflow technique in dogs during halothane anesthesia. Dexmedetomidine was given in a dose (10 micrograms/kg) reported to reduce the anesthetic requirement of halothane by 90%. During 0.9% halothane anesthesia dexmedetomidine caused a significant reduction in CBF without influencing the metabolic rate for oxygen. Reducing the halothane concentration to 0.1% caused no further change in CBF, but increased the metabolic rate for oxygen 19%. The cerebral vasoconstrictive effect, combined with the 90% reduction in MAC for halothane, indicates that dexmedetomidine might be a useful adjunct to inhalation anesthetics during neurosurgery in situations where an increase in CBF should be avoided.

Asymmetrical autonomic dysfunction of the feet after retroperitoneal surgery in patients with testicular cancer: 2 case reports.

We report on 2 patients with hyperhidrosis and decreased temperature of the leg on the unoperated side after unilateral retroperitoneal lymph node dissection. Both patients had a 4 to 5C difference in skin temperature of the feet, with the operated side being warm and dry compared to the nonoperated side. This condition is most likely due to a lesion of sympathetic fibers or ganglia located in close proximity to the retroperitoneal lymph nodes, resembling a unilateral lumbar sympathectomy. In addition, both patients had profuse sweating and a subjective feeling of coldness of the leg on the nonoperated side, which caused considerable discomfort. This latter phenomenon most likely represents a compensatory sympathetic hyperfunction due to the decreased sympathetic function in the other leg.

Raynaud's phenomenon after combination chemotherapy of testicular cancer, measured by laser Doppler flowmetry. A pilot study.

The pathophysiology of Raynaud's phenomenon after Cisplatin-Bleomycin-Vinblastine combination chemotherapy, its relationship to polyneuropathy, and response to transcutaneous nerve stimulation (TNS), was studied in eight patients previously treated for testicular cancer. Peripheral circulation in the index finger was measured by laser Doppler flowmetry before and after cold provocation. In all patients there was an exaggerated and prolonged vasoconstrictor response to cold, with a mean flux reduction of 61%, and a mean restitution time of greater than 7 min, characteristic of Raynaud's phenomenon of the vasospastic type. The normal controls had a mean flux reduction of 24% and a restitution time of 1.5 min. Clinical examination and nerve conduction measurements revealed a mild polyneuropathy in five of the eight patients, but an etiological relationship with Raynaud's phenomenon could not be ascertained. There was no measurable effect of TNS.

Cerebral effects of nitrous oxide when added to low and high concentrations of isoflurane in the dog.

The purpose of this canine study was to examine the cerebral vascular and metabolic effects of adding nitrous oxide to isoflurane from 1.4% expired (1 MAC) up to a concentration giving an isoelectric electroencephalogram (EEG). Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were determined using a sagittal sinus outflow technique. At 1.4% expired isoflurane, 70% nitrous oxide increased CBF but had no effect on CMRO2. At 3.1% expired isoflurane, 70% nitrous oxide had no effect on either CBF or CMRO2. The latter concentration of isoflurane rendered the EEG isoelectric, but when nitrous oxide was added, EEG activity reappeared. To again produce an isoelectric EEG required an increase in the isoflurane concentration to 3.5% +/- 0.2% (with no further effect on CMRO2). The authors also found that at 1.4% isoflurane, 0.9 micrograms.kg-1.min-1 of angiotensin significantly decreased CMRO2 without any effect on CBF. It is concluded that nitrous oxide, when added to isoflurane concentrations ranging from 1.4% to 3.5% in the dog, increases CBF at the low but not the high isoflurane concentrations although it has no effect on CMRO2.

Bulbar myoclonus without palatal myoclonus. A hypothesis on pathophysiology.

A 40-year-old woman with myoclonic contractions bilaterally in the infrahyoid neck muscles, especially in the left cricothyroid muscle, was presented and successfully treated with botulinum toxin injections. The patient had a wide, aberrant vessel curving into the left dorsolateral reticular formation of the medulla oblongata. Based on our observations, we propose that symptomatic bulbar and palatal myoclonus is caused by pathology in the dorsolateral reticular formation, and not by inferior olivary dysfunction as is currently thought.