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The cerebral cortex reorganizes in response to central or peripheral lesions. Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a - albeit finally ineffective - mechanism to compensate for the ongoing loss of motor neurons in ALS.

Background: Patients with ALS commonly exhibit pseudobulbar affect., Methods: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140)., Results: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q., Conclusions: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Objective: To assess the association of enteroviruses (EV) with ALS by applying a sensitive seminested reverse transcription (RT) PCR protocol to the detection of enteroviral RNA in a blinded set of archived tissues from ALS and control cases., Methods: The specimen set consisted of 24 frozen spinal cord samples from ALS cases, 17 frozen spinal cord samples from negative control (non-ALS) cases, and 5 frozen spinal cord positive control samples. The positive controls were two human spinal cord samples spiked with poliovirus (PV) and three spinal cords from PV-infected transgenic mice. A sensitive, EV-specific, seminested RT-PCR assay was used to detect EV genome in RNA extracted from the specimens and controls., Results: The assay detected EV RNA in a 10(-5) dilution of infected mouse tissue. EV RNA was not detected in the ALS specimens or in specimens from control cases, despite the presence of amplifiable RNA as assessed by amplification with control primers, whereas all of the positive control specimens yielded the expected PV amplification product., Conclusion: The reported association between EV infection and ALS was not confirmed by testing this set of specimens with these sensitive methods.

Motor fatigue, during 30 seconds of maximum voluntary isometric contraction (MVIC) was simultaneously evaluated by the decline in mechanical force output, and from the compression in the power spectrum obtained from surface electromyogram (sEMG). Measurements were performed in patients diagnosed with amyotrophic lateral sclerosis (ALS) and normal control (NC) in two muscle groups, elbow flexors (EF) and ankle dorsiflexors (DF). The decline in force output, as a manifestation of mechanical fatigue, was digitally calculated online by partitioning the force versus time curve to determine the percent of MVIC reduction over a 30 sec period and was expressed as force fatigue index (FFI). The compression in the sEMG power spectrum, as a manifestation of myoelectrical fatigue, was tracked by calculating the median frequency shift (MFS) from the first 5 sec to the last 5 sec of the 30 sec MVIC using digital Fast Fourier Transformation. In ALS patients, the significantly higher reduction in mechanical force output during the 30 sec MVIC (higher FFI) was accompanied with significantly less compression in the sEMG power spectrum (less MFS) as compared to NC (P < or =0.005) in the two muscle groups. This dissociation between the mechanical and myoelectrical manifestation of muscle fatigue in ALS indicates that a reduction in muscle fiber conduction velocity (MFCV) may be a contributing peripheral factor in the pathogenesis of muscle fatigue in ALS. Alterations in motor unit functionality, especially in type II fast motor unit muscle fibers, and structural damage in denervated muscle fibers may contribute to the lower MFCV during motor fatigue in ALS patients.

Motor fatigue is a common complaint in patients with amyotrophic lateral sclerosis (ALS), but is often excluded, unlike weakness, from the clinical assessment of these patients. This could be due to the complexity and often painful assessment techniques of this motor deficit. This study examines the feasibility of quantitative assessment of motor fatigue by modifying presently available force measurements. The relationship between weakness and fatigue in ALS patients was also examined. Fifty-four ALS patients and 39 normal control subjects performed 30 s of sustained maximal voluntary isometric contraction (MVIC) of elbow flexors (EF), knee extensors (NE), and ankle dorsiflexors (DF), using a computerized force measurement system and standardized testing procedures. Fatigue index (FI) was digitally calculated, from the force-time curve, as the percentage of MVIC unable to be sustained over the 30-s period. Fatigue was greater in ALS patients than in normal control (mean=23% vs. 15%) in all muscles including muscles that were not clearly weak. Weakness and fatigue were poorly correlated in ALS patients and may be independent measures of the pathogeneses of ALS.

Functional magnetic resonance imaging (fMRI) provides high-resolution, non-invasive estimates of neural activity detected by a blood oxygen level dependent signal by assessing the increase in blood flow to the local vasculature that accompanies neural activity in the brain. fMRI studies with standard hand motor test (index-thumb opposition, ITO, or pinch) in ALS patients show good test-retest reliability and similar amplitude of signals in ALS patients compared with control subjects. Isometric force can be performed with careful control for the force exerted, recruitment of other muscles and motion artefact. The volume (number of voxels above threshold) of sensorimotor and cerebellar cortex activated by ITO is reproducibly larger in ALS patients compared with control subjects. Imagined movements in ALS have been studied, as in amputees, and larger volumes are activated in ALS patients with imagined movements as well, compared with control subjects. fMRI studies in ALS patients evaluating cortical activation during pure somatosensory stimulation cutaneous stimulation of the hand to elicit the palmomental response and cutaneous stimulation of the sole to elicit the plantar response - indicate that ALS patients activate a significantly smaller volume of the contralateral sensorimotor cortex compared to control subjects. No statistically significant difference was seen in other areas, including the ipsilateral cerebellum and the contralateral thalamus. An anterior shift in the volume of cortex activated by these paradigms occurs in ALS patients, with a volume of activation, anteriorly, not activated in control subjects. fMRI studies will complement other clinical neurophysiological and neuroimaging techniques in our future attempts to solve the riddle of ALS and other motor neuron diseases.

Objective: The ALS Patient Care Database was created to improve the quality of care for patients with ALS by 1) providing neurologists with data to evaluate and improve their practices, 2) publishing data on temporal trends in the care of patients with ALS, and 3) developing hypotheses to be tested during formal clinical trials., Background: Substantial variations exist in managing ALS, but there has been no North American database to measure outcomes in ALS until now., Methods: This observational database is open to all neurologists practicing in North America, who are encouraged to enroll both incident and prevalent ALS patients. Longitudinal data are collected at intervals of 3 to 6 months by using standard data collection instruments. Forms are submitted to a central data coordinating center, which mails quarterly reports to participating neurologists., Results: Beginning in September 1996 through November 30, 1998, 1,857 patients were enrolled at 83 clinical sites. On enrollment, patients had a mean age of 58.6 years +/-12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and 61% were men. The mean interval between onset of symptoms and diagnosis was 1.2+/-1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease-specific therapy (48%). Physical therapy was the most common nonpharmacologic intervention (45%). The primary caregiver was generally the spouse (77%). Advance directives were in place at the time of death for 70% of 213 enrolled patients who were reported to have died., Conclusions: The ALS Patient Care Database appears to provide valuable data on physician practices and patient-focused outcomes in ALS.

Background: In 1994 consensus guidelines were developed for conducting clinical trials in ALS. With growing experience in clinical trials, it has become clear that a number of further guidelines were needed., Methods: Under the auspices of the World Federation of Neurology Committee on Research, a multinational group of neurologists, statisticians, patient advocates, representatives from the pharmaceutical industry as well as regulatory agencies developed consensus about a number of revisions to the existing guidelines during a 2 day conference in April 1998., Results: Expanded areas of focus include greater protection of patient rights, more detailed guidelines for outcome measures statistical analyses, disclosure of study results and improved interaction between investigators and the corporate sector., Comment: Substantial progress has been made in standardizing and improving the quality of clinical trials in ALS through these consensus guidelines.

The El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis (ALS) were introduced in 1990 to provide a standardised and diagnostically reliable approach to the early recognition of this disease. It is still unclear, however, whether these are the best criteria available for the early diagnosis of ALS. We applied these criteria retrospectively to clinical material available from 34 cases of autopsy proven ALS in an attempt to validate their usefulness in a pathological series. The clinical material was reviewed and specific clinical signs and anatomical levels of involvement recorded. Only signs listed in the criteria were included in the analysis. The El Escorial criteria for clinically definite ALS demonstrated high sensitivity and accuracy when validated in this clinicopathological study. Neuroimaging and electromyography were important in shortening the time in which patients were given a diagnosis of clinically definite ALS. Other diagnostic dilemmas in ALS and the role of early diagnosis of this disease are discussed.

The advances in treatment for amyotrophic lateral sclerosis (ALS) have demonstrated the need to diagnose this disease precisely and directly. Two international initiatives, at El Escorial in 1990 and at Airlie House in 1998, have grappled with the clinical and laboratory elements that may accelerate the diagnostic process. Shortly after the Airlie House meeting in 1998, an international group of clinical neurologists met to discuss optimal management strategies in ALS. The goals were to examine current diagnosis and treatment pathways and to attempt to devise an algorithm that would foster early diagnosis, thus enhancing the possibility of optimal treatment.

The concept of earlier diagnosis of amyotrophic lateral sclerosis (ALS) requires in-depth investigation of its benefits and consequences. First, how good must a treatment be before ALS is determined to be a treatable condition? Analogy with cancer therapy suggests that a good quality of life after treatment is an essential feature of a "good" therapy. Survival in some diseases may be prolonged without a significant improvement in the patient's quality of life. Neurologists need to be clear about what they are trying to achieve in prolonging survival and maintaining a good quality of life for their patients with ALS. Second, can early diagnosis extend apparent survival in the absence of a therapeutic intervention that significantly affects the disease process? Earlier diagnosis on the basis of confirmed clinical signs and earlier institution of therapy may lead to a perception of improved survival, which is greater in young ALS patients. Third, can early diagnosis provide a benefit through prolongation of the time the patient remains able to work? Any therapeutic intervention to slow the early stages of the disease would benefit patients who wanted to maintain their self-esteem by continuing to work. Finally, earlier diagnosis of ALS requires decisions to be made concerning the acceptable rate of misdiagnosis, which at present reaches 10% false-positive and up to 44% false-negative.

As yet, there is no staging system for amyotrophic lateral sclerosis (ALS). One early attempt to define disease stages consisted of post-hoc analysis of the international, placebo-controlled, clinical trials of riluzole. In this analysis, five health states were defined for ALS (mild, moderate, severe, terminal, death) to determine whether therapeutic intervention with riluzole could favorably influence the time spent in the different stages. The time spent in the mild and moderate disease states (taken together) was considerably longer in patients treated with riluzole than in those treated with placebo (317 days compared with 242 days). Riluzole did not influence the median time in the mild, severe, or terminal ALS stages but did slightly shorten the time in the moderate ALS stage compared with placebo. In all the ALS stages, the 75th percentile of time in that state appeared to be extended. Survival analysis indicated that the relative risk was less than 1.0 with riluzole treatment in the moderate, severe, and terminal health states but not in the mild health state, when it remained at 1.0. The time to failure was longer in patients in the moderate, severe, and terminal ALS stages but was significantly longer only in the moderate ALS stage. These findings indicate that future studies of therapeutic intervention should examine rigorously defined stages of disease to examine end points other than death. The development of a staging system, analogous to the ones used in oncology, has implications for the concept of early diagnosis.

Motor neurons from the brain stems of amyotrophic lateral sclerosis (ALS) and control patients were examined with immunoantibodies to CuZn-superoxide dismutase (CuZnSOD) and Mn-superoxide dismutase (MnSOD). We found that there was a marked staining for CuZnSOD in all the motor nuclei, the hypoglossus, ambiguus, facialis and trigeminus from the ALS patients, but not in the controls. The same neurons from the ALS patients also stained very intensely for MnSOD, whereas the neurons from the control patients stained weakly or not at all. Loss of neurons was also a very consistent finding and was noted in all the motor nuclei from the ALS patients. There was a proliferation of glial cells which stained strongly both for CuZnSOD and for MnSOD accompanying the loss of the neurons. These results indicated that there was an apparent increase of superoxide dismutase immunoreactivity in motor neurons of ALS patients. We conclude that CuZnSOD and MnSOD immunoreactivity is increased in motor neurons and glia in the brain stems of patients with ALS, specific for the terminal phase of this disease.

The introduction of palliative therapies in amyotrophic lateral sclerosis (ALS) will alter the epidemiology of ALS as it is known now. Although incidence rates will remain unchanged in the near future, prevalence rates will likely increase dramatically. Better understanding of the age-specific presentation of motor neuron diseases worldwide will shed light on the vexing questions concerning the variable incidence rates in some countries and apparent incidence gradients in North America and Europe.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by significant speech and swallowing problems resulting from upper and lower motor neuron loss. Weakness is the primary ALS disease-related sign, and measures of muscle strength have revealed nonuniform patterns of muscle weakness in orofacial muscles. To a large extent, muscle strength measures in these studies have not been evaluated in terms of functional significance, and few researchers have addressed the relation between weakness and motor neuron loss. This study addressed whether multiple measures, including static isometric maximum voluntary contraction (MVC), a dynamic measure of the peak rate of change of force (PRCF), an upper motor neuron (UMN) index, and a functional disability score (FDS) might enhance understanding of speech dysfunction in ALS. Ten males diagnosed with sporadic ALS showing mild speech impairment and an equal number of matched controls were studied. Tongue MVC and PRCF were more impaired than those of the lip and jaw, irrespective of the time post onset and site of initial symptoms. Results also suggested that disproportionate tongue impairment may be related to UMN deficits. However, impairments in the rate of contraction did not appear to be related to UMN deficits. Tongue weakness and tongue and lower lip PRCF were related to the degree of speech severity, but none of the measures was related to speech intelligibility. The value of a functional outcome measure like speech intelligibility and its role in characterizing orofacial involvement in the early stages of ALS bulbar impairment are discussed.

We conducted this study to better inform amyotrophic lateral sclerosis (ALS) patients about home ventilation and to assist them in decision-making. We gathered data on the prevalence of ALS patients on home ventilation in northern Illinois and the percentage who chose it, and we asked identified subjects, their families, and physicians for their attitudes toward home ventilation. Fewer than 10% of ALS patients had chosen home ventilation, and fewer than 5% were still on it. Seventeen patients (90%) were glad to have chosen home ventilation and would choose it again. Family caregivers reported major burdens, and only half would choose it for themselves. The mean yearly cost of home ventilation was $153,252. Home ventilation is effective for ALS patients had desired by the small number who undergo it, but it imposes significant burdens on families.

Speech intelligibility and its phonetic and acoustic correlates were studied in a group of 10 women with amyotrophic lateral sclerosis (ALS). Intelligibility assessment with a word-identification test indicated that the most disrupted phonetic features pertained to velopharyngeal valving, lingual function for consonant contrasts of place and manner, and syllable shape. An acoustic signature analysis based on trajectories of the first and second formants in selected monosyllabic test words revealed that the mean slope of the second formant (F2) was reduced compared with that of a normal geriatric control group. This F2 slope reduction is interpreted to reflect loss of lingual motoneurons. Acoustic measures of phonatory function for sustained vowel prolongation demonstrated abnormalities in fundamental frequency, perturbations of frequency (jitter) and amplitude (shimmer), and signal-to-noise ratio. The data for women with ALS are compared with data for a normal geriatric control group of women and with data for a group of 25 men with ALS (Kent et al., 1990). Although the overall ranking of errors was similar for males and females with ALS, men were more likely to have impairments of voicing in syllable-initial position.

Few detailed reports have been published on the nature of speech and voice changes during the course of amyotrophic lateral sclerosis (ALS). The subject of this case study is a woman who was diagnosed as having ALS with bulbar signs at the age of 53. Speech intelligibility, pulmonary function, and selected speech and voice functions were tested during an approximately 2-year course of her disease. Over this period, her speech intelligibility, as measured by a multiple-choice word identification test, declined from 98% to 48%. Phonetic features that were most affected during the intelligibility decline included voicing contrast for syllable-initial and syllable-final consonants, place of articulation contrasts for lingual consonants, manner of articulation for lingual consonants, stop versus nasal manner of production, features related to the liquid consonants, and various features related to syllable shape. An acoustic measure, average slope of the second-formant frequency, declined in association with the intelligibility reduction and is thought to reflect the loss of lingual motoneurons. Her pulmonary function also declined over the observation interval, with particularly severe reduction in measures of air flow. Oral diadochokinesis and measures of vocal function (including jitter, shimmer, and signal-to-noise ratio) were highly variable across test sessions. These results are discussed in terms of the challenges they present to sensitive assessment of change and to management of the communication disability in ALS.

ALS symptom spread results from local spread of the neuronal degeneration because contiguous areas are more quickly involved than non-contiguous areas. Local spread to contiguous areas of motor neuron dysfunction is faster at the brainstem, cervical and lumbar regions than spread to non-contiguous areas. The time for caudal-rostral symptomatic spread of ALS to involve a distant region is a function of the distance of that region from the site of onset. The time for spread to the bulbar region is shorter following arm onset than leg onset. Spread to non-contiguous areas is faster within the spinal cord than from the spinal cord to the bulbar region. These kinetics are consistent with axonal transport of the etiological agent in a manner similar to spread of poliovirus in poliomyelitis patients. Spread from the bulbar region to the spinal cord, on the other hand, occurs faster than symptom spread from the limb region to the bulbar region in limb onset patients. This rapid limb involvement following bulbar onset is more dramatic in males compared with females. Females with leg onset, on the other hand, show more rapid involvement of the opposite leg, either arm or bulbar structures than males. Gender effects may determine the course of ALS depending on the original site of onset.

Speech intelligibility was studied in a group of 25 male patients with amyotrophic lateral sclerosis (ALS). The object of the study was to determine the phonetic impairments underlying the speech intelligibility deficits that frequently accompany ALS. Analyses with a word intelligibility test indicated that the most disrupted phonetic features involved phonatory (voicing contrast) function, velopharyngeal valving, place and manner of articulation for lingual consonants, and regulation of tongue height for vowels. The mean error proportion for the five most severely affected features correlated highly (0.97) with the intelligibility score (percent correct). The phonetic feature analyses are one index of bulbar muscle impairment in amyotrophic lateral sclerosis and also may help to direct the speech management in these individuals.

From 1975 to 1983, six cases of amyotrophic lateral sclerosis (ALS) were diagnosed in long-term residents of Two Rivers, Wis; the probability that this occurred due to chance was less than .05. To investigate potential risk factors for ALS, we conducted a case-control study using two control subjects matched to each case patient for age, gender, and duration of residence in Two Rivers. Physical trauma, the frequent consumption of freshly caught Lake Michigan fish, and a family history of cancer were reported more often by case patients than control subjects. These findings support previous studies proposing a role for trauma in ALS pathogenesis and suggest that the causative role of diet should be further explored. Continued surveillance for and epidemiologic investigation of ALS clusters with subsequent retrospective analysis may provide clues concerning the cause of ALS.

Focal, small-to-moderate and transient improvement occurred in the muscle strength and function of patients with ALS who received TRH in dose-response and screening studies. In a small pilot study of 12 patients, 3 months administration of TRH at 10 mg per kg on alternate days resulted in localized increased strength of jaw muscles as well as significant improvement in lower extremity function. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH. Autonomic effects of TRH on heart rate, respiration, and blood pressure were not serious and attenuated slightly over the course of the study.

Physical work capacity in 35 ALS patients and 6 untrained controls was evaluated during progressive bicycle ergometry. In the ALS patients, maximum oxygen consumption (VO2max) and work capacity (Wmax) drop in relation to the decrease in ALS functional score. However, the oxygen cost (ml O2/kpm) of submaximal exercise was significantly increased. Prolonged submaximal exercise tests in six ALS patients and six matched untrained controls indicated that the exercise-induced increase in plasma free fatty acids, beta-hydroxybutyrate, esterified carnitine, and muscle esterified carnitine was significantly retarded in ALS patients.

Facial, trigeminal, and hypoglossal motoneuron involvement was quantified in 25 amyotrophic lateral sclerosis patients and in normal controls. Measures included (1) maximum voluntary contraction of the lower lip, mandible, and tongue using custom-designed force transducers, (2) clinical functions of each muscle group, and in some patients (3) orofacial mobility using videofluoroscopy. All measures indicated that the tongue muscles were most severely affected, even in patients who initially had symptoms in the extremities.

Familial amyotrophic lateral sclerosis (FALS) constitutes 5 to 10% of cases of ALS and, in most families, its inheritance is consistent with an autosomal dominant trait with age-dependent penetrance. The biochemical abnormality underlying the disorder is unknown. We analyzed DNA from 131 members of 6 multigenerational ALS families, which included 13 affected members, for genetic linkage to 39 expressed and DNA markers, using the techniques of 2-point linkage analysis, multilocus linkage analysis, and exclusion mapping. We identified FALS families with structures suitable for linkage, by computer simulation techniques. A DNA bank established to provide optimum use of available FALS families provided DNA from immortalized lymphoblast cell lines and frozen postmortem tissue. We could not link FALS to any of the markers studied, but excluded chromosome regions unlikely to be a locus of the FALS gene. With the help of this exclusion data, we will concentrate on regions of the human genome that remain unexcluded.

Patients with amyotrophic lateral sclerosis have increased levels of the neutrotransmitter norepinephrine in blood and cerebrospinal fluid and depressed levels of the inhibitory neurotransmitter gamma-aminobutyric acid in cerebrospinal fluid. These neurochemical alterations are most marked in patients bedridden with advanced disease, appear interrelated, and lead to cardiovascular alterations in patients with amyotrophic lateral sclerosis.

Intravenous thyrotropin releasing hormone (TRH) was administered to 6 amyotrophic lateral sclerosis (ALS) patients at the dose rate of 10 mg/kg. Blood samples were obtained prior to and at 10, 20, 40, 60, and 120 min during the TRH infusions. Lumbar punctures were performed at 90 min following the start of infusion. The mean serum TRH concentration rose from 0.03 +/- 0.02 (SD) to 17 +/- 2 ng/ml by 60 min and remained constant to 120 min. The mean CSF TRH concentration rose 10-fold from 0.02 +/- 0.01 to 0.2 +/- 0.02 ng/ml at 90 min and increased further to 0.5 +/- 0.2 ng/ml at 120 min. Subcutaneous TRH was administered to 4 ALS patients at 2.5 mg/kg and to 5 ALS patients at 5.0 mg/kg. The mean serum TRH concentration increased to 1.4 +/- 0.6 ng/ml (2.5 mg/kg) and 3.2 +/- 1.1 ng/ml (5.0 mg/kg) by 60 min. The mean CSF TRH concentration at 60 min increased to 0.3 +/- 0.08 ng/ml following 2.5 mg/kg TRH and 0.8 +/- 0.04 ng/ml following 5.0 mg/kg TRH. TRH entry into the CSF is comparable following subcutaneous or intravenous administration.

Serum and CSF from 48 patients with amyotrophic lateral sclerosis and six patients with late-onset postpoliomyelitis progressive muscular atrophy were investigated for the presence of antibody to poliovirus types 1, 2, and 3, coxsackie viruses B3 and B4, influenza A, measles, rubella, mumps, herpes simplex types 1 and 2, cytomegalovirus, varicella-zoster, and Toxoplasma gondii. These results were compared with those from 53 control patients with neuromuscular disease matched for age, sex, race, and poliovirus vaccine exposure. There was no difference either in distribution of serum or CSF antibody titers or the geometric-mean antibody titers. There was no evidence suggesting the presence of locally produced specific viral antibody within the CNS to any of the agents studied. In particular, there was no serological evidence to suggest an association between persistent infection with any poliovirus type and amyotrophic lateral sclerosis or late-onset postpoliomyelitis progressive muscular atrophy.

The critical points that must be addressed in evaluating ergotropic drugs are exemplified by the current morass of positive and negative results that have been obtained in clinical investigations of TRH or its analogues. Appropriate subject selection is crucial. These patients may have bulbar symptoms, and those features of ALS should be specifically assayed for treatment effects relative to placebo. Gender-specific effects of TRH need to be accounted for in study design. In addition, electrophysiological techniques such as single fiber density may help determine the responsiveness of patients to TRH or its analogues. The clinical significance of an increase in fiber density following TRH or other drugs should be determined, as it will provide insight into the state of motor neurons in the spinal cord of patients with ALS and possibly could be important in determining those who may respond to TRH if such a response is possible. Clinical studies have quite clearly shown conflicting results. Basic studies, however, have shown that response to TRH is state dependent, that is, whether the patient is male or female. Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues.