EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias

Cluster headache and the other trigeminal‐autonomic cephalalgias [paroxysmal hemicrania, short‐lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome] are rare but very disabling conditions with a major impact on the patient's quality of life. The objective of this study was to give evidence‐based recommendations for the treatment of these headache disorders based on a literature search and consensus amongst a panel of experts. All available medical reference systems were screened for any kind of studies on cluster headache, paroxysmal hemicrania and SUNCT syndrome. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies resulting in level A, B or C recommendations and good practice points. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7 l/min over 15 min and 6 mg subcutaneous sumatriptan are drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy or tolerability). Although no class I or II trials are available, steroids are clearly effective in cluster headache. Therefore, the use of at least 100 mg methylprednisone (or equivalent corticosteroid) given orally or at up to 500 mg i.v. per day over 5 days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as alternative treatments. Surgical procedures, although in part promising, require further scientific evaluation. For paroxysmal hemicranias, indomethacin at a daily dose of up to 225 mg is the drug of choice. For treatment of SUNCT syndrome, large series suggest that lamotrigine is the most effective preventive agent, with topiramate and gabapentin also being useful. Intravenous lidocaine may also be helpful as an acute therapy when patients are extremely distressed and disabled by frequent attacks.     

Paroxysmal eyelid movements in patients with visual‐sensitive reflex seizures

Aim. Paroxysmal eyelid movements (PEM) are non‐epileptic episodes characterized by eyelid closure, upturning of the eyes, and rapid eyelid flutter. The aim of this study was to report clinical and EEG data of patients with PEM and its relationship with visual sensitivity. Methods. We studied 26 patients with epilepsy (12 males and 14 females; mean age: 14.0±6.9 years) who presented PEM. The epilepsy was idiopathic generalized (eight cases), idiopathic focal (six cases), symptomatic focal (five cases), and reflex epilepsy (seven cases). PEM and blinking were analysed by video‐EEG recordings at rest and during intermittent photic stimulation, pattern stimulation, and TV watching. Blink rate was evaluated during three different conditions: at rest, during a TV‐viewing period, and at the occurrence of PEM. Analysis of variance (ANOVA) was used for statistical comparisons. Results. Repeated episodes of PEM were recorded in all patients. The frequency of PEM ranged from 8 to 12.5 Hz (average: 9.6±1.5). PEM were accompanied by a significant increase in blinking compared to the rest condition and TV watching (blink rate: 56.5±21.1 vs 25.0±16.2 vs 11.3±11.8, respectively; p<0.0001). Photoparoxysmal EEG responses (measured as sensitivity to photic stimulation) were found in 25 cases, associated with pattern sensitivity in 22; only one patient was sensitive to pattern but not photic stimulation. Visually‐induced seizures were recorded in 20 cases, triggered by both stimuli (photic and pattern stimulation) in 11 patients; seizures were triggered by pattern stimulation (but not photic stimulation) in five, photic stimulation (but not pattern stimulation) in three, and TV watching (but not photic or pattern stimulation) in one. Epileptic eyelid myoclonia was noted in 17 patients. Conclusion. The coexistence of PEM, photoparoxysmal EEG responses, increased blinking, and epileptic eyelid myoclonia suggests an underlying dysfunction involving cortical‐subcortical neural networks, according to the recent concept of system epilepsies. [Published with video sequences]     

Primary Sjogren''s syndrome presenting with generalized autonomic failure

A 64 year-old woman developed Raynaud's phenomenon and dry eyes/mouth. Laboratory examination revealed positive Schirmer's test, rheumatoid factor and anti-nuclear antibody, and lymphocytic sialoadenitis on salivary gland biopsy. These features strongly suggested the diagnosis of primary Sjogren's syndrome. Three years later, she gradually developed generalized autonomic failure without apparent sensory neuropathy on nerve conduction study. She had systolic pressure fall of 51 mmHg on head-up tilt test, cardiovascular supersensitivity to diluted norepinephrine infusion, cardiac denervation in [123I]-MIBG scintigraphy, impaired R-R variability, decreased sweating and prolonged colonic transit time. Autoimmune autonomic ganglionopathy was mostly responsible for her autonomic failure.     

Sleep movements and associated autonomic nervous activities in patients with Parkinson''s disease

Nine parkinsonian patients were studied during one night using the static charge sensitive bed (SCSB) method for the monitoring of respiration, ballistocardiogram (BCG) and body movements. The parkinsonian sleep was more restless than that of the controls. As the SCSB-defined levels of autonomic nervous activity were concerned, the amount of motor active wakefulness (MAW) was significantly (P less than 0.05) increased in parkinsonian patients, who also had less quiet sleep (P less than 0.05) than the controls. Parkinsonian tremor was present during 29.8 +/- 15.8% of the time in bed. Usually it was observed during wakefulness; it disappeared when the patient fell asleep. The frequency of turning-over events in bed was smaller in the parkinsonian patients than in the controls (P less than 0.05). When the heart rate changes associated with sleep movements were studied it was found that the parasympathetic deceleration component in the parkinsonian patients was absent. The motor dysfunction associated with Parkinson's disease is reflected in many ways in the sleep movement activity. Sleep disturbances in PD seem to be secondary in character; i.e. they can be due to impaired motor functions like turning around in the bed, or due to impaired arousal mechanisms during sleep.     

Clinical and subclinical autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy

Autonomic neuropathy, although common in Guillain-Barré syndrome, is considered rare in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and has not been systematically investigated in that disorder. The present study was aimed at determining the prevalence of autonomic dysfunction and investigating the integrity of autonomic nervous system (ANS) reflexes in CIDP. We studied 17 patients with idiopathic CIDP and 20 healthy controls. Six quantitative autonomic function tests (AFTs) were used: Valsalva ratio, 30/15 ratio, and inspiration-expiration difference for parasympathetic function; and tilt test, handgrip test, and sympathetic skin response for sympathetic function. Eleven patients had symptoms of autonomic dysfunction. AFTs were abnormal in 13 patients. Parasympathetic and sympathetic systems were affected with equal frequency. The tilt test was abnormal most frequently, followed by the 30/15 ratio. Three patients developed postural hypotension with loss of consciousness during the tilt test. Abnormality of AFTs did not correlate with the presence of dysautonomic symptoms; duration, severity, and clinical course of the disease; or with age or gender of patients. Our study suggests a higher frequency of clinical and subclinical involvement of the ANS in CIDP than previously estimated. Dysautonomic symptoms are frequent but are mild. However, upon prolonged passive standing, autonomic failure can lead to loss of consciousness. The subclinical involvement of the ANS affects mainly the sympathetic vasomotor and parasympathetic cardiovascular fibers.     

Chronic inflammatory demyelinating polyradiculoneuropathy with autonomic involvement

We report a case of chronic acquired neuropathy predominantly affecting sensory and autonomic nerves. Investigations showed a demyelinating polyradiculoneuropathy with axonal degeneration and depletion of postganglionic noradrenergic fibers in the rectal mucosa. Intravenous immunoglobulin and corticosteroid administration were effective in alleviating symptoms and improving electrophysiological abnormalities. This neuropathy may be a novel variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), in which autoimmunoreactivity is directed not only against myelin but also against axon- or ganglion-composing protein. Autonomic nerve involvement does not exclude a diagnosis of CIDP.     

Cardiovascular autonomic function and sympathetic skin response in chronic inflammatory demyelinating polyradiculoneuropathy

Quantitative cardiovascular autonomic function tests (AFTs) and sympathetic skin response (SSR) were performed in 12 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Parasympathetic autonomic function was examined by Valsalva ratio and R-R interval variation during rest and deep breathing. Sympathetic autonomic function was evaluated by blood pressure responses to sustained handgrip and active standing. Using quantitative AFTs, subclinical autonomic dysfunction was demonstrated in three (25%) patients. Abnormal SSR was seen in six (50%) patients. Thus, mild autonomic dysfunction is present in many CIDP patients. The autonomic abnormalities involve parasympathetic or sympathetic components; in the sympathetic nervous system, both vasomotor and sudomotor fibers may be involved.     

Autonomic function in patients with chronic fatigue syndrome

Subtle signs of autonomic dysfunction and orthostatic intolerance have been reported in patients with chronic fatigue syndrome (CFS). To assess cardiovascular autonomic function noninvasively in an unselected group of patients with CFS, we examined responsiveness to several cardiovascular reflex tests in 37 CFS patients and 38 healthy control subjects. Blood pressure and heart rate (HR) were recorded continuously by a Finapres device before and during forced breathing, standing up, Valsalva maneuver, and sustained handgrip exercise (HG). In addition, a mental arithmetic test was carried out and questionnaires to assess the severity of CFS symptoms were completed. At rest, there were no significant differences in blood pressure or in HR between the two groups. The in- and expiratory difference in HR tended to be lower in CFS patients (28.4±10.5 beats) than in healthy controls (32.2±9.5) (p=0.11). The maximal increase in HR during standing up was not significantly different between the CFS group (37.6±8.9 beats) and the control group (40.2±8.9 beats). There were no significant differences between both groups with regard to the Valsalva ratio, but the systolic and diastolic blood pressure responses were significantly larger in CFS patients, despite the fact that many CFS patients were not able to sustain the Valsalva maneuver. The HR response to MA was significantly less in the CFS group (22.6±9.9) than in the control group (29.5±16.7) (p<0.05), suggesting impaired cardiac sympathetic responsiveness to mental stress. The lower HR responses could not be explained by the level of concentration in the CFS group. During HG exercise, the hemodynamic responses were lower in the CFS group than in the control group, but this might be attributed to the lower level of muscle exertion in CFS patients. There were no significant differences between CFS patients with and without symptoms of autonomic dysfunction regarding the hemodynamic responses to the cardiovascular reflex tests. The findings of the study suggest that there are no gross alterations in cardiovascular autonomic function in patients with CFS.     

Relationship between the frequency of autonomic dysfunction and the severity of chronic obstructive pulmonary disease

OBJECTIVE: The relationship between the frequency of autonomic dysfunction (AD) and the severity of chronic obstructive pulmonary disease (COPD) has not been exactly known, despite its importance in the pathogenesis of COPD. Therefore, we aimed to evaluate the relationship between the clinical stage severity of the disease and the frequency of AD in COPD patients. METHODS: The frequency and type of AD were determined according to the clinical severity of 35 stable COPD patients. The results were compared between the mild and moderate-severe COPD groups. Sympathetic system (SS) was evaluated with sympathetic skin response (SSR), QT and QTc intervals (ms) analyses. Parasympathetic system was evaluated with the heart rate interval variations (RRIV). RESULTS: For the total group, an AD was detected in 20 patients (57%), a parasympathetic dysfunction (PD) in 14 (40%), a mixed-type dysfunction in five (14%) and a sympathetic dysfunction (SD) in only one patient (3%). For the 12 mildly affected patients, there were cases of isolated SD in only one patient (8.5%), isolated PD in five (42%) and AD in six patients (50%). For the 23 moderate-severe COPD patients, mixed AD was detected in five patients (22%), isolated PD in nine (39%) and AD in 14 patients (61%). There were no significant differences between the two patient groups, neither for isolated parasympathetic and sympathetic, mixed form nor for total AD (P>0.05). CONCLUSIONS: The results suggested that PD was dominant in patients with COPD. However, the frequencies of autonomic parasympathetic and sympathetic dysfunction did not increase significantly with the severity of COPD. The severity of hypoxemia and/or airflow limitation may not be the only unique or definite reason for AD in COPD, as there was not an exact correlation between the presence of AD and the severity of airflow limitation and hypoxemia.     

Epilepsy with eyelid myoclonia in the setting of de novo pathogenic variant in ATP1A3

Mutations in the ATP1A3 gene have been associated with several syndromes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. In this clinical commentary, we report a 2-year-old female patient with de novo pathogenic variant in the ATP1A3 gene associated with an early-onset form of epilepsy with eyelid myoclonia. The patient had frequent eyelid myoclonia occurring 20–30 times per day, without loss of awareness or other motor manifestations. EEG showed generalized polyspikes and spike-and-wave complexes maximal in the bifrontal regions, with prominent eye closure sensitivity. A sequencing-based epilepsy gene panel revealed a de novo pathogenic heterozygous variant in ATP1A3. The patient showed some response to flunarizine and clonazepam. This case highlights the importance of considering ATP1A3 mutations in the differential diagnosis of early-onset epilepsy with eyelid myoclonia and the potential benefit of flunarizine in improving language and coordination development in patients with ATP1A3-related disorders.     

Characterization of autonomic dysfunction in patients with irritable bowel syndrome using fingertip blood flow

Abstract  Fingertip blood flow (FTBF) as measured by laser Doppler flowmetry (LDF) measurement is considered an indicator of sympathetic nerve function. We evaluated autonomic function in patients with irritable bowel syndrome (IBS) by assessing FTBF with both LDF and continuous-wave (cw) Doppler sonography. Firstly, the two methods were compared in 40 healthy volunteers. Next, 59 patients with IBS as well as 118 healthy volunteer controls were studied. In the supine position, FTBF in the right index finger was measured with cw Doppler sonography, whereas FTBF in the left index finger was assessed with LDF. After baseline measurement for at least 5 min, the volunteers received sympathetic stimulation from cold stress applied without notification in the form of an icebag (0 °C) upon the left forearm for 1 min. The new cw Doppler sonography method can be used in place of the old LDF method for clinical purposes. FTBF velocity before stimulation ( V _pre) was significantly lower in the IBS group than that in the healthy volunteers ( P  < 0.01). In addition, the time required for FTBF to return to V _pre after stimulation was significantly longer in the IBS group than that in the control group. ( P  = 0.02). Thus, measurement of FTBF with cw Doppler sonography can be useful in the assessment of sympathetic nerve function. The IBS patients showed an abnormal FTBF response suggesting the presence of excess sympathetic activity.     

Cardiac autonomic function during submaximal treadmill exercise in adults with Down syndrome

This study determined whether the cardiac autonomic function of adults with Down syndrome (DS) differs from that of nondisabled persons during submaximal dynamic exercise. Thirteen participants with DS and 12 nondisabled individuals performed maximal and submaximal treadmill tests with metabolic and heart rate (HR) measurements. Spectral analysis of HR variability was performed on the last 256 consecutive R-R intervals obtained under the following conditions: (1) rest, (2) submaximal treadmill exercise (at constant relative intensity below the ventilatory threshold) and (3) recovery. Participants with DS presented lower chronotropic response than those without DS to peak and submaximal exercise (p < 0.05). Nevertheless, the fractional utilization of peak HR during treadmill walking was similar between groups (∼60% peak HR). Even though there were no between-group differences at rest or during recovery, the participants with DS showed a higher LF/HF ratio during exercise (p < 0.05). Similarly, the LF power of participants with DS during exercise was greater than that of nondisabled participants (p < 0.05). In contrast, both groups exhibited similar HF power at each physiological condition. In conclusion, these findings suggest that adults with DS demonstrate appropriate vagal withdrawal, but heightened sympathetic modulation of HR variability at ∼60% of their peak HR. Despite this, the absolute change in HR from rest to exercise was attenuated in these individuals compared to persons without disabilities. This indicates that DS may be associated with poor cardiac responsiveness to changes in autonomic modulation during exercise at intensities below the ventilatory threshold.     

Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non–small‐cell lung cancer

We report the case of a 55‐year‐old man with non–small‐cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal 2 years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 mm Hg supine and 66/47 mm Hg standing after 10 minutes) without a compensatory heart rate increase (57 to 59 beats per minute), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness, and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with an absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04. Plasma norepinephrine level was low (79 pg/ml supine, 330 pg/ml standing). Single‐fiber electromyography of the right extensor digitorum communis revealed normal mean consecutive difference (jitter) but several pairs exceeded a jitter of 100 μs. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02 nmol/L] and ganglionic AChR (0.34 nmol/L, normal <0.02 nmol/L) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mm Hg standing, 66 to 79 beats per minute), to Valsalva (normal blood pressure overshoot, hazard ratio 1.47), norepinephrine (194 pg/ml supine, 763 pg/ml standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that shows improvement with non‐supine rest. Muscle Nerve, 2009     

Clinical and physiological characteristics of autonomic failure with Parkinson's disease

We analyzed the clinical and physiological features of autonomic failure with Parkinson's disease (AF-PD) in seven patients and compared them with those of autonomic failure with multiple system atrophy (AF-MSA). In AF-PD, parkinsonism was more gradually progressive than in AF-MSA, and symptoms were responsive to L-dopa. All seven patients with AF-PD had orthostatic hypotension, postprandial hypotension, and constipation, but no urinary retention. Of these, three had hypohidrosis and five had frequent urination; five patients had subnormal plasma norepinephrine (NE) concentrations. Supersensitivity to NE infusion was observed in all patients. Head-up tilting (HUT) test resulted in no increase of plasma NE concentrations in both groups, but a significant increase of the plasma arginine vasopressin (AVP) concentrations in the patients with AF-PD. Urodynamic studies revealed that urinary bladder function was relatively well preserved in AF-PD in contrast to AF-MSA. In conclusion, there exists some clinical and physiological differences in autonomic features between AF-PD and AF-MSA, and postganglionic involvement predominates in AF-PD.     

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel

Objective

The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis.

Methods

An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM.

Results

There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic–clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy.

Significance

This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.     

Comparison of heart rate variability in patients with chronic fatigue syndrome and controls

Recent studies have reported a close association between chronic fatigue syndrome and neurally mediated hypotension. We hypothesized that this association may result from an abnormality in autonomic function among patients with chronic fatigue syndrome, which may be detectable using an analysis of heart rate variability. We prospectively studied 19 patients who fulfilled the Centers for Disease Control criteria for chronic fatigue syndrome and 11 controls. Each subject underwent a two-stage tilt-table test while wearing a Holter monitor. Heart rate variability was assessed in the supine baseline position and during upright tilt using frequency domain parameters. In the baseline supine position, high frequency (HF) power, low frequency (LF) power, and the ratio of low frequency power to high frequency power (LF/HF ratio) were similar. In both patient groups, upright tilt resulted in a similar decrease in HF power, increase in LF power, and increase in the LF/HF ratio. In conclusion, autonomic function, as assessed using an analysis of heart rate variability, does not differ in the baseline supine state, nor in response to upright tilt among patients with chronic fatigue syndrome and healthy controls.