Richard K. Olney

Are amyotrophic lateral sclerosis patients cognitively normal

Background: Patients with ALS are often told that the disease spares cognition; however, recent evidence suggests deficits in frontal executive skills occur in a sizable minority of ALS patients. In many instances, the frontal executive deficits represent the co-occurrence of frontotemporal lobar dementia (FTLD) and ALS. Methods: Word generation, a simple frontal task that takes <2 minutes, was tested in 100 consecutive patients with ALS seen in the authors’ multidisciplinary clinic. Any patient with a prior dementia diagnosis was excluded from the study. A subset of 44 patients agreed to undergo further neuropsychological testing and clinical interview to confirm or deny a diagnosis of dementia. Results: Diminished word generation was found in one-third. Of the patients with abnormal word generation who agreed to further evaluation, nearly all were shown to meet research criteria for FTLD. In addition, one-quarter of the patients with normal word generation who agreed to further evaluation met research criteria for FTLD; these patients had new-onset personality changes. Conclusions: This study suggests that frontal executive deficits are present in half of ALS patients, many of whom meet strict research criteria for FTLD. Word generation tests are a useful screening tool in this cohort.

Charcot‐Marie‐Tooth disease and related neuropathies: Mutation distribution and genotype‐phenotype correlation

Charcot‐Marie‐Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N‐myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N‐myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT‐causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one‐third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.

Lamotrigine for HIV-associated painful sensory neuropathies: A placebo-controlled trial

Objective: To evaluate the efficacy and tolerability of lamotrigine (LTG) for the treatment of pain in HIV-associated sensory neuropathies. Methods: In a randomized, double-blind study, patients with HIV-associated distal sensory polyneuropathy (DSP) received LTG or placebo during a 7-week dose escalation phase followed by a 4-week maintenance phase. Randomization was stratified according to whether or not patients were currently using neurotoxic antiretroviral therapy (ART). Results: The number of patients randomized was 92 (62 LTG, 30 placebo) in the stratum receiving neurotoxic ART and 135 (88 LTG, 47 placebo) in the stratum not receiving neurotoxic ART. Mean change from baseline in Gracely Pain Scale score for average pain was not different between LTG and placebo at the end of the maintenance phase in either stratum, but the slope of the change in Gracely Pain Scale score for average pain reflected greater improvement with LTG than with placebo in the stratum receiving neurotoxic ART (p = 0.004), as did the mean change from baseline scores on the Visual Analogue Scale for Pain Intensity and the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain (p ≤ 0.02). The incidence of adverse events, including rash, was similar between LTG and placebo. Conclusions: Lamotrigine was well-tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy. Additional research is warranted to understand the differing response among patients receiving neurotoxic antiretroviral therapy compared with those not receiving neurotoxic antiretroviral therapy.

A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy

Objective: To investigate the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP). Background: The pathogenesis of HIV-associated DSP is unknown and there is no effective treatment. A novel anticonvulsant, lamotrigine, blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. There have been anecdotal reports of efficacy of lamotrigine in the treatment of painful neuropathy and trigeminal neuralgia. Methods: In a multicenter, randomized, double-blind, placebo-controlled study, lamotrigine was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Study duration was 14 weeks. The primary outcome measure was change in pain on the modified Gracely scale with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief. Results: Of 42 enrolled subjects, 13 did not complete the 14-week study endpoint. In five of these, rash was the cause for dropout. In the remaining 29 evaluable subjects, 20 patients received placebo and 9 received lamotrigine. The pain scores at baseline were not significantly different. The reduction in average pain from baseline to week 14 was greater (p = 0.03) in the lamotrigine group (−0.55) than in the placebo group (−0.18), adjusting for baseline levels of pain. There was no difference between the groups on the change in peak worst pain. Conclusions: In this small trial, lamotrigine showed promise in the treatment of pain associated with HIV-related DSP. The frequency of rash was greater than in lamotrigine studies in epilepsy. A larger controlled study of lamotrigine is warranted.

The effects of executive and behavioral dysfunction on the course of ALS

Objective: To determine whether patients with ALS–frontotemporal lobar dementia (FTLD) have a shorter survival and are less compliant with recommended treatments than those with ALS who have normal executive and behavioral function (classic ALS). Methods: Survival analysis from ALS symptom onset to death included 81 of 100 consecutive patients who could be classified definitely as ALS with abnormal executive or behavioral function or as classic ALS. Criteria were defined for compliance with noninvasive positive-pressure ventilation (NPPV) and percutaneous endoscopic gastrostomy (PEG). Results: Median survival was 2 years 4 months for the 28 patients with FTLD and 3 years 3 months for the 53 patients with classic ALS (relative hazard for death 1.93, CI 1.09 to 3.43; p = 0.024). However, the relative hazard associated with FTLD (1.49) in the multivariate model was diminished by the association of FTLD with bulbar onset and older age and was not significant in this sample size. With bulbar onset, median survival was 2 years 0 months for the 14 with ALS-FTLD and 2 years 10 months for the 10 with classic ALS (relative hazard for death 2.78, CI 1.02 to 7.55; p = 0.045), and older age was not a significant risk. Noncompliance with NPPV and PEG were 75% and 72% in ALS-FTLD, respectively, vs 38% and 31% in classic ALS (relative risks 2.00 and 2.34; p = 0.013 and 0.022). Conclusions: Survival is significantly shorter among patients with ALS-FTLD than with classic ALS. Furthermore, patients with ALS-FTLD are twice as likely to be noncompliant.

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: A randomized trial

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.

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis

Background: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. Methods: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. Results: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. Conclusion: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.

Evaluation of thermography in the diagnosis of selected entrapment neuropathies

We studied 20 normal subjects, 22 patients with carpal tunnel syndrome, and 15 with ulnar neuropathy at the elbow to compare the diagnostic accuracy of infrared thermography with that of conventional electrodiagnostic studies. We found abnormal thermograms in 55% of patients with carpal tunnel syndrome and 47% with ulnar neuropathy, using 2.5 SD from the normal mean as criteria for abnormality. The abnormalities consisted of either an increase in interside temperature difference in the fingers and hands or an alteration of the normal thenar-hypothenar temperature gradient in the fingers. The sensitivity of thermography was considerably lower than that of conventional electrodiagnostic methods. Moreover, the thermographic abnormalities were nonspecific, and could be misleading as they did not reliably identify the side of lesion or distinguish between median or ulnar nerve involvement. Thus, thermography is not helpful in the diagnosis of these two common entrapment neuropathies.

A comparison of magnetic and electrical stimulation of peripheral nerves

The utility of the magnetic coil for stimulation of the cervical spinal nerves was compared to electrical stimulation by a monopolar needle cathode placed onto the spinal lamina in six volunteers. No statistical difference in average amplitudes or areas of evoked CMAPs was found although the size of the magnetic coil evoked potentials was less at C7–8 in several subjects. Electrical stimulation resulted in depolarization at a more proximal site. Electrical stimulation was associated with more discomfort, especially at C5–6. We conclude that electrical stimulation using a monopolar needle as the cathode is the superior technique for the clinical electrophysiologic study of the proximal brachial plexus and cervical spinal nerves.We compared magnetic stimulation using different coil designs (2 rounded coils and a butterfly-prototype coil) with electrical stimulation of the median and ulnar nerves in 5 normal subjects. Using magnetic stimulation we were able to record technically satisfactory maximal sensory and motor responses only with the butterfly coil. Submaximal electrical stimuli preferentially activated sensory rather than motor axons, but submaximal magnetic stimuli did not. The onset latency, amplitude, area and duration of responses elicited electrically or magnetically with the butterfly coil during routine sensory and motor nerve conduction studies were similar, and motor and sensory conduction velocities were comparable when studied over long segments of nerve. However, the motor conduction velocities with magnetic and electrical stimulation differed by as much as 18 m/sec in the across-elbow segment of ulnar nerve. Thus, recent developments in magnetic stimulator design have improved the focality of the stimulus, but the present butterfly coil design cannot replace electrical stimulation for the detection of focal changes in nerve conduction velocity at common entrapment sites, such as in the across-elbow segment of the ulnar nerve.

Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome

A retrospective literature review of the electrodiagnosis of myasthenia gravis (MG) and Lambert–Eaton myasthenic syndrome (LEMS) through July 1998 was performed for the purpose of generating evidence‐based practice parameters. There were 545 articles identified, of which 13 articles met at least three of the six criteria set previously by the American Association of Electrodiagnostic Medicine (AAEM). An additional 21 articles were identified from review articles or the references of these first 13 articles leading to a total of 34 articles. Results of studies utilizing repetitive nerve stimulation (RNS) showed that a 10% decrement in amplitude from the first to fourth or fifth intravolley waveform while stimulating at 2–5 HZ is valid for the diagnosis of MG. The degree of increment needed for the diagnosis of LEMS is at least 25% but most accurate when greater than 100%. Abnormal jitter or impulse blocking are the appropriate criteria for diagnosis of neuromuscular junction (NMJ) disorders when using single fiber electromyography (SFEMG). SFEMG is more sensitive than RNS for the diagnosis of disorders of neuromuscular transmission, but may be less specific and may not be available. Therefore, RNS remains the preferred initial test for MG and LEMS.