A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

ALS diagnostic criteria of El Escorial Revisited: do they meet the needs of clinicians as well as researchers?

The El Escorial criteria for diagnosis of amyotrophic lateral sclerosis (ALS) have been in use for almost a decade. A revised set of criteria, meant to supersede the original set, was developed at a 1998 World Federation of Neurology (WFN) ALS meeting at Airlie House in Warrenton, Virginia, USA. This revised document, nicknamed El Escorial Revisited, has been published on the WFN-ALS website. El Escorial has proven useful in standardizing diagnostic criteria for entry into research trials and it is expected that El Escorial Revisited will help to liberalize such entry requirements. However, general neurologists and neuromuscular clinicians have found El Escorial to be unwieldy and generally unhelpful in achieving an earlier, accurate diagnosis of ALS. The El Escorial Revisited document is a step toward lessening these problems, but more 'user-friendly' criteria may be necessary for clinicians and those not conducting research. Such ALS criteria would improve categorization of ALS patients, would allow clinicians more latitude in beginning ALS treatment, and would educate practitioners to differentiate ALS from other motor neuron and non-motor neuron diseases. Intensive education of physicians will help improve earlier patient referral and accurate ALS diagnosis. There remains a group of 'difficult cases' that will continue to challenge the neuromuscular specialist. Earlier diagnosis in this latter group will require significant advances in the fields of electrodiagnosis, neuroimaging, immunobiochemistry, and neurogenetics.

Diagnostic challenges in ALS.

Although the essential requirements for diagnosis of amyotrophic lateral sclerosis (ALS) are clearly defined by the El Escorial criteria, many physicians, including neurologists, still miss the diagnosis. Physician misdiagnosis of ALS relates to lack of knowledge about ALS and skill and to diagnostic difficulty. The differential diagnosis must exclude nonmotor neuron diseases and other adult-onset motor neuron diseases with restricted presentations, e.g., progressive bulbar palsy (pure bulbar), progressive muscular atrophy (pure lower motor neuron) and primary lateral sclerosis (pure upper motor neuron), ALS-like syndromes and ALS variants, and adult-onset spinal muscular atrophies. Although the diagnosis of ALS remains a clinical one, laboratory testing can be used to exclude other diseases and to confirm the diagnosis. Such tests include EMG and nerve conduction studies, MRI and CT of the spine and brain, identification of biochemical markers in blood and CSF, and muscle or nerve biopsy. Genetic testing can identify gene defects in some types of familial ALS and in certain other inherited motor neuron diseases that mimic ALS. At present there is no widely accepted protocol for laboratory testing in cases of suspected ALS, but it is hoped that laboratory tests will improve in the future to facilitate earlier confirmation of a diagnosis of ALS. However, correct and early diagnosis of ALS can only be achieved when the first, second, or third physician who sees the patient knows about ALS and includes it in a differential diagnosis.

ALS diagnostic criteria, El Escorial, and Philip II of Spain: a historical perspective.

El Escorial, a magnificent palace-monastery in central Spain, was the setting in 1990 for a meeting of ALS experts who developed a consensus document called the El Escorial ALS Diagnostic Criteria. El Escorial was originally conceived by the Spanish Habsburg monarch, Philip II (1527-1598), as an elaborate burial place for his parents, Emperor Charles V and Isabella. It soon became a symbol of the Spanish empire and Philip's Catholic leadership of the Counter-Reformation. El Escorial included a monastery, palace, basilica, mausoleum, seminary, library, and hospital. Nothing was spared by Philip in obtaining the finest examples of religious art, architecture, music, and books. Philip, as absolute monarch, inherited a vast empire which stretched over Europe, Asia, North Africa, and the New World. His style of personal micro-management and poor economic planning hampered his ability to manage both national and foreign affairs. Philip had a special interest in medicine, including royal hospitals, improved government standards for physicians, medicinal plants, and the health benefits of alchemy and sacred relics. El Escorial's grand scale has generated both illustrious praise and critical condemnation over the last four centuries. Its place in Spanish and world history is assured.

The amyotrophic lateral sclerosis (ALS) patient perspective on misdiagnosis and its repercussions.

We studied the rate of initial "misdiagnosis', along with factors than might distinguish such patients, in 64 patients with amyotrophic lateral sclerosis (ALS) who completed a survey of 34 questions. Announcement of the survey was made by electronic newsletter and users group bulletin board directed at ALS patients. The questionnaire was distributed to interested ALS patients via electronic mail (e-mail), and 64 ALS patients (81% from the USA) returned their completed questionnaires via reply e-mail or postal mail. Seventeen patients (27% of total group) indicated at least 1 prior misdiagnosis, most commonly spinal stenosis/radiculopathy; 5 listed unnecessary and costly surgical treatments (laminectomy, endarterectomy). Misdiagnosis appeared to be more common in patients above age 60 and may be more common in patients originating in cities versus smaller communities. Mean time from onset of first symptom until definitive diagnosis of ALS was prolonged in patients with initial misdiagnosis (19 months) compared with non-misdiagnosed patients (10 months). Such a previous misdiagnosis may decrease a patient's chance of acceptance into multicenter ALS drug trials.

Follow-up study of risk factors in progressive supranuclear palsy.

The cause of progressive supranuclear palsy (PSP) is not known and has been little studied. The one previous controlled epidemiologic survey, performed at our center in 1986, found small-town experience and greater educational attainment as PSP risks, but, in retrospect, these results may have been produced by ascertainment bias. Since that time, several anecdotal reports have implicated heredity and various environmental exposures in the cause of some cases of PSP. To clarify the results of the previous study and to evaluate the more recently implicated candidate factors in a controlled fashion, we mailed a validated 69-item questionnaire to 91 personally examined patients with PSP and 104 unmatched controls with other neurologic conditions for which they had been referred to our tertiary neurologic center. We were able to match 75 subjects from each group by year of birth, sex, and race and subjected them to a separate matched-pair analysis. We allowed surrogates to supply any or all of the responses. Questions concerned hydrocarbon, pesticide, and herbicide exposure; urban/rural living; auto repair and other occupations; head trauma; educational attainment; maternal age; and family history of PSP, parkinsonism, dementia, and other neurologic conditions. A statistically significant finding was that patients with PSP were less likely to have completed at least 12 years of school (matched odds ratio = 0.35, 95% CI = 0.12-0.95, p = 0.022; unmatched odds ratio = 0.44, 95% CI = 0.21-0.89, p = 0.020). We hypothesize that this result may be a proxy for poor early-life nutrition or for occupational or residential exposure to an as-yet unsuspected toxin. Future studies should examine these potential risk factors in PSP.

Percutaneous magnetic coil stimulation of the phrenic nerve roots and trunk.

We describe a technique of percutaneous magnetic coil (MC) stimulation of the phrenic nerve trunk on one side of the neck and phrenic roots over the upper cervical vertebral column in 10 normal subjects and 2 patients. We were able to obtain compound muscle action potentials (CMAPs) from the diaphragm at two sites (xiphoid process and 7th intercostal space) after stimulation of the phrenic nerve trunk and roots. We noted that the onset latencies after phrenic root stimulation remained fixed despite increasing the stimulus intensity from 50% to 100% and on moving the MC vertically or laterally, suggesting that stimulation of the fastest conducting fibers was occurring at a fixed site, most likely at the intervertebral foramina. Absent responses unilaterally in one and prolonged latencies to diaphragmatic CMAPs in another patient confirmed phrenic neuropathy in these patients.

Magnetic brain stimulation: safety studies.

We describe short-term and long-term safety studies after low repetition rate magnetic brain stimulation in 10 normal subjects. We obtained quantitative EEG data, psychometric test results, serum prolactin and cortisol levels before and after brain stimulation. EEG and psychometric data were also obtained in 5 of these subjects 16-24 months after the initial experiment. Short- and long-term studies did not show any deleterious effects. Randt delayed recalls, however, showed a transient reduction in the score immediately after stimulation which resolved on retesting in 2 weeks. To address the question of fatigue we repeated Randt tests in 4 subjects before and after magnetic brain stimulation but without the other extensive psychometric, EEG and blood tests. Pre- and post-stimulation scores on this occasion showed no significant difference in these 4 subjects suggesting that the transient changes in the previous Randt score were related to fatigue. We conclude that single-pulse magnetic brain stimulation has no deleterious effects after magnetic brain stimulation.

Pulmonary function at diagnosis of amyotrophic lateral sclerosis. Rate of deterioration.

The purpose of this study was to determine the degree of respiratory muscle impairment in patients with newly diagnosed amyotrophic lateral sclerosis (ALS) and the subsequent rate of decline of respiratory function. Thirty-one of 36 patients had respiratory muscle weakness at presentation, although only 7 complained of any respiratory symptoms. Vital capacity (percent predicted) was significantly lower in the symptomatic group (55.9 +/- 20.3) compared with the asymptomatic group (76.4 +/- 21.0). Respiratory muscle impairment as measured by vital capacity (percent predicted) was related to stage of disease at presentation. Rate of decline of respiratory muscle strength as measured by VC (-3.5 percent/month), negative inspiratory pressure (NIF) (+2.9 cm H2O/month), and positive expiratory pressure (PEP) (-3.4 cm H2O/month) tended to be linear with a great deal of interpatient variability. It is concluded that early measurement of respiratory muscle strength in ALS with subsequent follow-up studies may be useful in determining overall prognosis and in decision making.

Magnetic coil stimulation of the human lumbosacral vertebral column: site of stimulation and clinical application.

We describe the technique of magnetic coil (MC) stimulation of the lumbosacral roots and the possible site of stimulation in 22 control subjects, and the clinical usefulness of MC stimulation in 5 patients with low back pain. We observed 2 components in the compound muscle action potential of the soleus muscle following MC stimulation over the lumbosacral region. The second component had the physiological properties of the H reflex. The conduction time from the anterior horn cells of the lumbosacral spinal cord to the site of nerve root stimulation over the lumbosacral vertebral column was indirectly calculated as between 3.9 and 4.1 msec. Assuming a conduction velocity of 50 m/sec this would represent a distance of approximately 20 cm from the spinal motor neurons. Based on our control and patient data we conclude that the MC stimulation may be an useful technique for the diagnosis of lumbosacral radiculoplexopathy.

Anterior femoral cutaneous nerve injury following femoral artery reconstructive surgery.

Two cases are presented exhibiting symptoms and signs of bilateral anterior femoral cutaneous nerve injury, clinically sparing femoral nerve branches to the saphenous nerve and quadriceps muscles. This occurred following surgical dissection in the femoral triangles associated with femoral artery reconstructive surgery. Anterior femoral cutaneous nerve injury should be considered when anterior medial thigh pain and numbness occur following aortofemoral bypass graft surgery and other types of femoral artery reconstructive surgery.

Misdiagnosis in patients with amyotrophic lateral sclerosis.

To confirm our impression that a high percentage of patients with amyotrophic lateral sclerosis are initially misdiagnosed, we reviewed records of 33 patients with a definitive diagnosis of amyotrophic lateral sclerosis seen over 10 years. Fourteen patients (43%) were initially misdiagnosed. Mean time to correct diagnosis was significantly greater for the misdiagnosed group (16.0 +/- 9.3 months) than for the rest of the patients (7.6 +/- 4.1 months). Two of three patients with an initial symptom of dyspnea were misdiagnosed. Three patients underwent laminectomies because of misdiagnosis. Age, stage of disease, and unusual presenting symptoms were not identified as causes of misdiagnosis. Most likely causes were physicians' failure to consider the diagnosis and lack of familiarity with the common clinical presentations of amyotrophic lateral sclerosis. Earlier diagnosis of amyotrophic lateral sclerosis may help prevent medical mismanagement and may benefit patients both medically and psychologically.

Effect of inspiratory resistance and theophylline on respiratory muscle strength in patients with amyotrophic lateral sclerosis.

The effect of breathing through inspiratory flow resistive loads ranging between 4.5 and 27.0 cm H2O/L/s was assessed in eight patients with amyotrophic lateral sclerosis (ALS) and in eight control subjects. ALS patients developed respiratory muscle fatigue manifested by significant declines in negative inspiratory pressure (18.3%), vital capacity (7.2%), and peak inspiratory flow rate (5.5%). Control subjects did not fatigue with these resistances. In ALS patients, theophylline increased respiratory muscle strength after resistive breathing as manifested by an increase in negative inspiratory pressure (28.2%), vital capacity (10%), and peak inspiratory flow rate (11.8%). It is concluded that in patients with ALS, the already weakened respiratory muscles are easily fatigued. Furthermore, theophylline can strengthen loaded respiratory muscles in patients with ALS.

Short-latency somatosensory evoked potentials in brain-dead patients.

Ten adult brain-dead patients were evaluated for the presence of clearly defined median nerve short-latency somatosensory evoked potentials (SSEPs). All met clinical criteria recommended by the President's Commission report (1981), had positive apnea tests, and had electrocerebral silent EEGs. P13-P14 and N20 were absent in all scalp-scalp channels, although 3 patients showed P13-P14 in scalp-non-cephalic channels. Of 6 patients showing N13, 3 lacked P13-P14. Our data suggest a characteristic destruction of N20 and rostral P13-P14 generators, with variable rostral-caudal loss of lower generators. SSEPs can provide valuable information about brain-stem activity in the evaluation of suspected brain-dead patients.

Apnea testing in brain death.

A standardized protocol was followed in 33 apneic oxygenation tests on 20 patients suspected of being brain dead. Spontaneous respiratory movements developed in just one patient; this patient was the only one who did not show electrocerebral silence on electroencephalography. Significant hypoxemia, hypotension, or cardiac arrhythmias were not encountered despite lung disease in 14 of our 20 patients. The apnea test protocol employed proved to be safe and sensitive. With a starting partial arterial carbon dioxide pressure greater than or equal to 36 mm Hg and a disconnection time from the ventilator of ten minutes in a normothermic patient (greater than or equal to 36.1 degrees C [greater than or equal to 97 degrees F]), the pressure threshold of 60 mm Hg should be reached in all patients.

Posterior rhythmic slow activity in EEG after eye closure.

During a 20 month period, EEGs in 7 patients, ages 6-16 years, showed a distinctive posterior rhythmic slow (PRS) activity brought on by eye closure. Following eye opening for 5-10 sec, eye closure on command was followed by a rhythmic high amplitude (100-250 microV) slow wave discharge of 3-4 c/sec lasting for 1.5-3 sec after a latency of 300-500 msec. Its distribution was limited to the occipital, posterior temporal and parietal regions. It was always bilaterally synchronous, occurred symmetrically or asymmetrically and fatigued easily. Of the 7 initial EEGs, only 2 had other EEG abnormalities. One patient, in a subsequent EEG, developed spontaneous PRS unrelated to eye closure. Clinical histories on the 7 patients showed 5 with various types of seizure disorders, 1 with attention deficit disorder, and 1 with Tourette syndrome. Neurological examination was normal in all patients, while computerized tomography or radioisotope brain scan was normal in 4. We suggest that PRS after eye closure represents a variant of the non-specific spontaneously occurring PRS described by Aird and Gastaut and others. It was found only in children and was not found to be helpful in diagnosing a seizure disorder or structural abnormality. Furthermore, such a discharge should not be interpreted as epileptiform activity.