Diagnostic criteria for amyotrophic lateral sclerosis: A multicentre study of inter-rater variation and sensitivity.

OBJECTIVE: This study assesses inter-rater agreement and sensitivity of diagnostic criteria for amyotrophic lateral sclerosis (ALS). METHODS: Clinical and electrophysiological data of 399 patients with suspected ALS were collected by eleven experienced physicians from ten different countries. Eight physicians classified patients independently and blinded according to the revised El Escorial Criteria (rEEC) and to the Awaji Criteria (AC). Inter-rater agreement was assessed by Kappa coefficients, sensitivity by majority diagnosis on 350 patients with follow-up data. RESULTS: Inter-rater agreement was generally low both for rEEC and AC. Agreement was best on the categories "Not-ALS", "Definite", and "Probable", and poorest for "Possible" and "Probable Laboratory-supported". Sensitivity was equal for rEEC (64%) and AC (63%), probably due to downgrading of "Probable Laboratory-supported" patients by AC. However, AC was significantly more effective in classifying patients as "ALS" versus "Not-ALS" (p < 0.0001). CONCLUSIONS: Inter-rater variation is high both for rEEC and for AC probably due to a high complexity of the rEEC inherent in the AC. The gain of AC on diagnostic sensitivity is reduced by the omission of the "Probable Laboratory-supported" category. SIGNIFICANCE: The results highlight a need for initiatives to develop simpler and more reproducible diagnostic criteria for ALS in clinical practice and research.

Effect of neck flexion on somatosensory and motor evoked potentials in Hirayama disease.

UNLABELLED: Hirayama disease (HD) is a rare motor disorder mainly affecting young men, characterized by atrophy and weakness of forearm and hand muscles corresponding to a C7-T1 myotome distribution. The weakness is usually unilateral or asymmetric and progression usually stops within several years. The etiology of HD is not well understood. One hypothesis, mainly based on MRI findings, is that the weakness is a consequence of cervical flexion myelopathy. The aim of this study was to explore the function of corticospinal and ascending somatosensory pathways during neck flexion using evoked responses. MATERIALS AND METHODS: 15 men with HD and 7 age-matched control male subjects underwent somatosensory evoked potentials (SSEP) and motor evoked potentials (MEP) studies with the neck in neutral position and fully flexed. SSEP studies included electrical stimulation of median and ulnar nerves at the wrist, and tibial nerve at the ankle with recording over the ipsilateral Erb's point, cervical spine, and contralateral sensory cortex. MEP recordings were obtained by magnetic stimulation of the motor cortex and the cervical lower spinal roots; the evoked responses were recorded from the contralateral thenar and abductor hallucis muscles. RESULTS: MEP recordings demonstrated significant lower amplitudes, and slightly prolonged latencies in HD patients on cervical stimulation, compared to control subjects. During neck flexion, MEP studies also demonstrated a statistically significant drop in mean upper limb amplitude on cervical stimulation in HD patients, as well as in control subjects, although to a lesser degree. In contrast, no significant differences were found in SSEP studies in HD patients compared to control subjects, or between neutral and flexed position in these groups. CONCLUSION: The study shows a negative effect of cervical flexion on MEP amplitudes in HD patients as well as in control subjects, requiring more studies to investigate its significance. Neck flexion did not have an influence on any SSEP parameters in patients or controls.

Postradiation lower motor neuron syndrome: case series and literature review.

A variety of neurological syndromes has been described after irradiation of the distal spinal cord and cauda equina, mainly as treatment for testicular cancer and lymphoma. One of these syndromes is a rare lower motor neuron syndrome, manifested by flaccid paraparesis. Medical files of patients with postradiation lower motor neuron syndrome treated in our neuromuscular clinic from 2005 to 2012 were reviewed. The diagnosis was based on past irradiation of the distal spinal cord and cauda equina, slowly progressive lower limb weakness, characteristic electrophysiological studies, and no alternative diagnosis. In addition, a systematic review of the literature on similar cases was performed using PUBMED. We identified five patients with postradiation lower motor neuron syndrome in our clinic charts. Three of them were irradiated due to seminoma, and the other two due to lymphoma. 45 additional similar cases were found in a literature search, mainly male (89 %), with testicular cancer (67 %), irradiated at mean age of 33 years, with an average irradiation dose of 5,225 cGy (range 3,000-14,600), and a latency period between irradiation and symptoms onset ranging from 3 months to 27 years (average 9 years). Magnetic resonance imaging was done only in few, showing gadolinium enhancement of the cauda equina in close to half of them (7/16). Our patients and those previously described in the literature form a distinct clinical and electrophysiological syndrome that might be more frequent then previously expected, and should be not overlooked.

Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes.

OBJECTIVE: To assess the evolution and life expectancy in patients with oculopharyngeal muscular dystrophy (OPMD) who are homozygotes for two (GCN)13 expansions in the PABPN1 encoding gene. BACKGROUND: OPMD is particularly frequent among French Canadians (FCs) and Uzbek Jews (UJs), who carry a same size, (GCN)13, PABPN1 mutation. The high rate of consanguinity among UJs together with late disease onset and normal fertility results in homozygous cases. METHODS: For 15 to 20 years, we followed 4 FC and 6 UJ homozygotes with OPMD and compared them with their heterozygous parents and siblings. In addition to clinical evaluation, electrodiagnostic tests, psychological tests, and brain imaging studies were performed. RESULTS: In all (GCN)13-(GCN)13 patients, OPMD started before age 35 years, with bilateral ptosis and dysphagia; external ophthalmoparesis and dysphonia followed within a few years, as well as weakness in proximal limb muscles. All patients had recurrent aspirations and lost weight; 4 patients required surgical interventions to alleviate dysphagia, and 5 required feeding gastrostomies. Most patients were followed by psychiatrists due to cognitive decline, recurrent depression, or psychotic episodes. Six patients died at ages 50, 51, 53, 56, 56, and 57 years. The eldest patient is now 51 years old; she is cachectic and requires special diet and psychiatric care for paranoid psychosis and uninhibited behavior. CONCLUSIONS: Oculopharyngeal muscular dystrophy progresses faster in homozygote compared with heterozygote patients. It is not restricted to the muscles, but also involves the CNS with cognitive decline and psychotic manifestations and leads to a reduced life expectancy.

Low uric acid levels in serum of patients with ALS: further evidence for oxidative stress?

BACKGROUND: The exact cause of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress is one of the factors implicated in the etiology of ALS as well as in that of other neurodegenerative diseases. Uric acid is an important natural antioxidant that may reduce oxidative stress. The objective of this study was to prospectively determine the serum uric acid levels in ALS patients and allegedly healthy individuals and to correlate those values with measures of ALS disease progression among the patients. METHODS: The ALS patients and well-matched controls underwent blood tests for serum uric acid levels which were then correlated with the patients' disability status, as expressed by the ALS Functional Rating Scale (ALSFRS-R). RESULTS: Eighty-six ALS patients and 86 well-matched controls participated. The ALS patients' mean+/-SD uric acid level was significantly lower (4.78+/-1.3 mg/dl) than that of the controls (5.76+/-1.26 mg/dl) (p<0.0001). The findings were similar for a second examination performed after an interval of at least 6 months. There was a correlation between the relative decrease of serum uric acid levels among patients (the difference between the patients' level and the controls' level) and the rate of disease progression (ALSFRS-R decline) (p<0.0001, r=0.624). CONCLUSIONS: ALS patients had lower serum uric acid levels than healthy individuals. The decreased uric acid levels were correlated to the rate of disease progression (ALSFRS-R decline), further demonstrating the possible role of oxidative stress in the induction and propagation of the disease.

Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To prospectively determine the intensity of systemic low-grade inflammation in patients with amyotrophic lateral sclerosis (ALS). PATIENTS AND METHODS: Patients with ALS and matched healthy controls underwent blood tests for inflammation-sensitive biomarkers: erythrocyte sedimentation rate (ESR), quantitative fibrinogen, wide-range C-reactive protein (wrCRP) concentrations, leukocyte count and neutrophil-to-lymphocyte ratio (NLR). The correlation between these inflammatory biomarkers and disability status of the patients, expressed by the ALS Functional Rating Scale (ALSFRS-R), was evaluated. RESULTS: Eighty patients with ALS and 80 matched controls were included. wrCRP, fibrinogen, ESR and NLR values were significantly elevated in patients compared with controls. There was a significant correlation between the ALSFRS-R score and wrCRP, ESR and fibrinogen levels. This correlation persisted on sequential examinations. CONCLUSIONS: A systemic low-grade inflammation was detected in patients with ALS and correlated with their degree of disability. A heightened systemic inflammatory state is apparently associated with a negative prognosis in ALS.

Cross-cultural variation in mental health at end of life in patients with ALS.

OBJECTIVE: To examine mental health at the end of life among patients with ALS in three countries: Israel, Germany, and the United States. METHODS: Patients met criteria for definite or probable ALS and had forced vital capacity (FVC) <60% of predicted. Patients completed nonsomatic items from the Beck Depression Inventory and visual analogue scale ratings. RESULTS: The three sites contributed a total of 92 patients; 60 died during follow-up. Patients at the three sites did not differ significantly in sociodemographic features or ALS Functional Rating Scale-Revised summary disability score; sites differed in use of nasal ventilation but not percutaneous esophageal gastrostomy (PEG) tube placement. In analyses that adjusted for disability and use of nasal ventilation, patients at the three sites differed in reports of pessimism and suffering; American patients reported the least distress and Israeli patients the most. In analyses limited to people who died, similar patterns emerged, with wish to live greatest in Americans and least among Israelis. These models adjusted for disability and days until death. CONCLUSIONS: Cultural factors may affect mental health at the end of life in patients with ALS.

Evoked potential studies in the antiphospholipid syndrome: differential diagnosis from multiple sclerosis.

BACKGROUND: The CNS manifestations of the antiphospholipid syndrome (APS) can mimic multiple sclerosis both clinically and radiologically. OBJECTIVE: To compare evoked potential studies in APS patients and patients with multiple sclerosis with similar neurological disability. METHODS: 30 APS patients with CNS manifestations and 33 patients with definite multiple sclerosis and similar neurological disability underwent studies of visual evoked potentials (VEP), somatosensory evoked potentials (SSEP) in the upper and lower limbs (UL, LL), and sympathetic skin responses (SSR) in the upper and lower limbs. RESULTS: The neurological manifestations in the APS patients included stroke (n = 17), transient ischaemic attacks (n = 10), and severe headache with multiple white matter lesions on brain MRI (n = 3). Abnormal SSEP (LL), and SSR (UL; LL) were seen in APS patients (37%, 27%, and 30%, respectively) but VEP and UL SSEP were rarely abnormal (10% and 6%, respectively in APS v 58% and 33% in multiple sclerosis; p = 0.0005, p = 0.008). Mean VEP latencies were more prolonged in multiple sclerosis (116 ms v 101 ms, p<0.001). Only one APS patient had abnormal findings in all three evoked potential studies, compared with seven patients in the multiple sclerosis group (p = 0.04) CONCLUSIONS: Abnormal VEPs are uncommon in APS in contrast to multiple sclerosis. Coexisting abnormalities in all other evoked potentials were similarly rare in APS. In patients with brain MRI findings compatible either with multiple sclerosis or APS, normal evoked potential tests, and especially a normal VEP, may support the diagnosis of APS.

R-R interval variation in Parkinson's disease and multiple system atrophy.

OBJECTIVE: To investigate whether the cardiac R-R interval variation (RRIV) is of value in differentiating patients with Parkinson's disease (PD) from multiple system atrophy (MSA). BACKGROUND: RRIV assessment is a simple procedure, reflecting mainly vagal efferent activity. Reduced RRIV was reported in MSA. METHODS: RRIV at rest and after 120 s of deep breathing was assessed blindly to clinical diagnosis in 22 PD and 20 MSA patients. The results were compared with data from 23 age-matched healthy subjects. RESULTS: RRIV at rest was 7.1 +/- 2.7% in PD and 9.7 +/- 7.2% in MSA, increasing after deep breathing to 11.2 +/- 6.3 and 12.3 +/- 6.6% correspondingly. The frequency of the RRIV abnormalities in the PD group (4/22, 18.2%) and MSA (6/20, 30%) were higher than among controls (P < 0.004). CONCLUSIONS: RRIV, either at rest or after deep breathing, may be abnormal both in PD and MSA, but does not distinguish between these disorders.

The value of muscle exercise in patients with amyotrophic lateral sclerosis.

The role of physical activity for patients with amyotrophic lateral sclerosis (ALS) is controversial. Twenty-five ALS patients were randomized to receive a moderate daily exercise program (n=14) or not to perform any physical activity beyond their usual daily requirements (n=11). At baseline and after 3, 6, 9 and 12 months, patients were assessed by manual muscle strength testing, the Ashworth spasticity scale, ALS functional rating scale (FRS), fatigue severity scale, a visual analogue scale for musculoskeletal pain and the quality-of-life scale (SF-36). At 3 months, patients who performed regular exercise showed less deterioration on FRS and Ashworth scales, but not on other parameters. At 6 months, there was no significant difference between groups, although a trend towards less deterioration in the treated group on most scales was observed. At 9 and 12 months, there were too few patients in each group for statistical evaluation. Our results show that a regular moderate physical exercise program has a short-lived positive effect on disability in ALS patients and should be recommended.

Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis.

APOE epsilon4 allele is associated with poorer outcome in degenerative neurological diseases. Its role in amyotrophic lateral sclerosis (ALS) is still unclear. The aim of the present study was to further analyze the association of APOE epsilon4 allele with progression and survival of ALS. One hundred consecutive ALS patients (53 males) and 133 controls were genotyped for the APOE epsilon4 allele. The association of this allele with survival to death or tracheostomy was analyzed by Kaplan-Meier survival analysis. The frequency of the APOE epsilon4 allele in ALS patients was slightly higher (15.1%) than in the control group (10.9%). Patients with or without an APOE epsilon4 allele had a similar age of onset and frequency of bulbar onset. There was a significant shortening of the 50% probability of survival (by 32 months) in patients carrying the APOE epsilon4 allele (p=0.03). In conclusion, carrying an APOE epsilon4 allele is a poor prognostic factor in ALS. This is compatible with a role of apolipoprotein on neuronal survival and repair.

The use of intravenous immunoglobulin as maintenance therapy in myasthenia gravis.

The standard therapy for myasthenia gravis (MG) includes steroids and immunosuppressants, which have delayed onset of action and significant side effects. Plasmapheresis and intravenous immunoglobulin have been used mostly for the treatment of severe exacerbations. In the present study we examined the use of intravenous immunoglobulin as maintenance treatment in MG. We included 11 patients with generalized myasthenia gravis. All had severe bulbar and respiratory involvement that required mechanical ventilation in three patients. Intravenous immunoglobulin treatment was initiated at a dose of 400 mg/kg/d for 5 days and followed by maintenance with 400 mg/kg once monthly. Regular medications were continued as necessary. There was significant improvement in all patients, and none required mechanical ventilation over the treatment period of 20.3 months +/- 8.3 (mean +/- SD, total patient years of treatment = 18.7). Steroid and pyridostigmine doses were reduced significantly and steroids were discontinued in two patients. There were no serious side effects related to intravenous immunoglobulin. These results suggest that intravenous immunoglobulin maintenance therapy is a valid modality in patients with MG.

Electrophysiologic evaluation of upper motor neuron involvement in amyotrophic lateral sclerosis.

BACKGROUND: The demonstration of upper motor neuron (UMN) dysfunction in patients with amyotrophic lateral sclerosis (ALS) with predominantly lower motor neuron (LMN) signs is clinically sometimes difficult. METHODS: We analyzed the possible role of F and H waves in the diagnosis of UMN dysfunction in 36 patients with different clinical forms of ALS and 20 controls. In both lower limbs we evaluated F-wave persistence and the F/M ratio of tibial nerves, Hmax/Mmax ratio, vibratory and recurrent (paired) inhibition of the H-reflex. RESULTS: The persistence of the F-response was decreased significantly in the LMN group only. The F/M amplitude ratio, vibrated-H/rest-H amplitude ratio and conditioned H/rest H amplitude ratio were significantly increased in patients with predominantly UMN, as well as in those with predominantly LMN signs. H/M amplitude ratios did not differ between the various patient groups. CONCLUSION: These findings show that ALS patients, including those without clinical evidence of UMN involvement, have a marked disinhibition of anterior horn motor neurons. The simple tests described could support an UMN abnormality when clinical signs are lacking, and help to establish a diagnosis sooner and more accurately.

Anal sphincter EMG does not distinguish between multiple system atrophy and Parkinson's disease.

Clinical distinction of multiple system atrophy (MSA) from Parkinson's disease (PD) is often difficult. Several recent reports indicate that objective classification may be accomplished using electromyographic (EMG) testing of the anal or urethral sphincters, but some authors have found that these tests are not reliable for this purpose. We studied 13 patients with PD and 10 with probable MSA, as diagnosed by consensus of four movement disorders specialists, according to accepted clinical criteria. Anal sphincter EMG was performed blind to the clinical diagnosis. We found no significant differences in the mean duration of motor unit potentials (MUPs), mean MUP amplitude, or prevalence of polyphasic potentials, satellite potentials, very long duration MUPs, or spontaneous activity between the two groups. Thus, anal sphincter EMG does not differentiate between PD and MSA.

Hypertriglyceridemia may cause a subclinical peripheral neuropathy.

Recently few patients with a painful neuropathy, attributed to extremely high triglyceride levels, were reported. In a prospective study, we evaluated 16 patients with marked hypertriglyceridemia without other causes of neuropathy, using nerve conduction and autonomic function tests. Six subjects (37%) showed mild signs of an asymptomatic motor and/or sensory and/or autonomic axonal polyneuropathy. The study demonstrates, that hypertriglyceridemia may be associated with a mild axonal polyneuropathy, usually subclinical, in significantly more patients than previously considered.

Antineurofilament antibodies in postpolio syndrome.

We determined the levels of antineurofilament antibodies in 29 patients with postpolio syndrome (PPS), 26 stable postpolio (PP) patients, 22 patients with ALS, and 20 normal controls (NCs). Patients with PPS had higher antibody levels to cholinergic neurofilaments than did all other groups. PP patients and those with ALS had antibody levels similar to those of NCs. The antibody binding level showed no relation to the age of the patients, duration of disease, or motor score.

Neurotoxicity of isolated limb perfusion with tumor necrosis factor.

Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNFalpha) is effective for advanced melanoma and sarcoma of the limbs. Ten patients undergoing HILP with TNFalpha were evaluated by neurological examinations, nerve conduction studies (NCS), sympathetic skin responses (SSR) and conventional and quantitative electromyography (EMG), performed before, 7 days and 6 weeks following HILP. Seven patients showed minimal clinical signs of peripheral nerve damage following HILP; in two the injury was evident electrophysiologically: 7 days following HILP five patients had paresthesias and/or hypoesthesia, one had a mild foot drop and one had autonomic disturbances in the affected limb. SSR was low in two patients in the affected limb, sensory nerve action potentials were not elicited in one, with normal motor NCS and EMG. At 6 weeks, four patients continued to have mild paresthesias and one had dysautonomia of the perfused limb. Sensory responses and SSR did not change, motor abnormalities were not found. These findings show that HILP with TNFalpha induces a mild, mainly sensory neuropathy in perfused limbs, not disturbing functionality and improving over time.

N30 somatosensory evoked potentials in patients with unilateral Parkinson's disease.

The N30 component of the somatosensory evoked responses (SEP) was reported as absent or abnormally low in various basal ganglia disorders, including Parkinson's disease (PD), but its relationship to the more affected side in asymmetric disease has not been assessed systematically. In 14 patients with unilateral PD and 10 controls, SEP were performed by stimulating each upper limb and recording from the parietal and frontal contralateral cortex. N30 was symmetric in 4 patients and 4 controls; it was asymmetric in 2 controls and in 8 patients (in 4 the responses were of lower amplitude over the affected hemisphere); no response was elicited in 2 patients and 4 controls. In all patients SEP were recorded off medication; in 9 of them the test was repeated following administration of L-dopa and did not show any significant changes. In conclusion, the N30 was asymmetric in a similar proportion of PD patients and controls. No correlation was found between the affected side and N30 latencies or amplitudes; no change was seen following L-dopa administration as well. The motor deficits and SEP abnormalities in PD probably reflect pathologies in different anatomical structures or functional circuits.