Background/Aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Methods: Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Results: Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. Conclusions: This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.

/pdf/microglial-activation-correlates-with-disease-progression-2si6w312hi.pdf

Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis.

Objective: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Methods: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score � 13 on the Center for Neurologic Studies–Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). Results: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p¼ 0.0002 and p¼ 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. Interpretation: DMq markedly reduced PBA frequency and severity, decreasing the condition’s detrimental impact on a patient’s life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA. ANN NEUROL 2010;00:000–000

Dextromethorphan Plus Ultra Low-Dose Quinidine Reduces Pseudobulbar Affect

Objective

To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients.



Methods

A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale.



Results

Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p ≤ 0.0077), quality of life (p < 0.0001), quality of relationships (p = 0.0001), and pain intensity score (p = 0.0271). DM/Q was well tolerated; only dizziness occurred with greater frequency than with placebo.



Interpretation

Results in multiple sclerosis patients were similar to those of a previous study in amyotrophic lateral sclerosis, demonstrating that DM/Q may be beneficial in treating potentially disabling pseudobulbar affect in a variety of neurological disorders. Ann Neurol 2006;59:780–787

Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.

Importance A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in amyotrophic lateral sclerosis (ALS). Objective To determine whether there are reductions in γ-aminobutyric acid (GABA) levels and elevations in glutamate-glutamine (Glx) levels in selected brain regions of patients with ALS by use of proton magnetic resonance spectroscopy. Design Case-control study using short echo time and GABA-edited proton magnetic resonance spectroscopy at 3 T with regions of interest in the left motor cortex, left subcortical white matter, and pons; data analyzed using logistic regression, t tests, and Pearson correlations; and post hoc analyses performed to investigate differences between riluzole-naive and riluzole-treated patients with ALS. Setting Tertiary referral center. Participants Twenty-nine patients with ALS and 30 age- and sex-matched healthy controls. Exposure Fifteen patients were taking 50 mg of riluzole twice a day as part of their routine clinical care for ALS. Main Outcomes and Measures Levels of GABA, Glx, choline (a marker of cell membrane turnover), creatine (a marker of energy metabolism), myo-inositol (a marker of glial cells), and N -acetylaspartate (a marker of neuronal integrity). Results Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls ( P N -acetylaspartate in the motor cortex ( P P P P P P P P P  ≤ .05 for both comparisons) than did riluzole-treated patients with ALS and healthy controls. Riluzole-naive patients with ALS had higher levels of N -acetylaspartate in the motor cortex than did riluzole-treated patients with ALS ( P Conclusions and Relevance There are reduced levels of GABA in the motor cortex of patients with ALS. There are elevated levels of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. These results point to an imbalance between excitatory and inhibitory neurotransmitters as being important in the pathogenesis of ALS and an antiglutamatergic basis for the effects of riluzole, although additional research efforts are needed.

https://jamanetwork.com/journals/jamaneurology/articlepdf/1699802/noi130056.pdf

An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy.

Pseudobulbar affect (PBA) may occur in association with a variety of neurological diseases, and so may be encountered in the setting of amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer’s disease, stroke, and brain tumors. The psychological consequences and the impact on social interactions may be substantial. Although it is most commonly misidentified as a mood disorder, particularly depression or a bipolar disorder, there are characteristic features that can be recognized clinically or assessed by validated scales, resulting in accurate identification of PBA, and thus permitting proper management and treatment. Mechanistically, PBA is a disinhibition syndrome in which pathways involving serotonin and glutamate are disrupted. This knowledge has permitted effective treatment for many years with antidepressants, particularly tricyclic antidepressants and selective serotonin reuptake inhibitors. A recent therapeutic breakthrough occurred with the approval by the Food and Drug Administration of a dextromethorphan/quinidine combination as being safe and effective for treatment of PBA. Side effect profiles and contraindications differ for the various treatment options, and the clinician must be familiar with these when choosing the best therapy for an individual, particularly elderly patients and those with multiple comorbidities and concomitant medications.

/pdf/pseudobulbar-affect-prevalence-and-management-48s00t0guv.pdf

Pseudobulbar affect: prevalence and management

Pharmaceutical compositions and methods for treating neurological disorders by administering same are provided. The compositions comprise dextromethorphan in combination with quinidine.

Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders

to neurologists to further characterize the disorder. When it became apparent that pseudobulbar affect could be moderated with treatment, the need for a quantitative test instrument became apparent. About 10 years ago Robinson and his colleagues developed the Pathological Laughing and Crying Scale (PLACS), an interviewer-administered rating scale that was validated for use in patients with cerebral vascular disease.2 This has been utilized as a trial endpoint in several studies of the effect of serotonin uptake inhibitors. 3,4 A modified version of PLACS has been developed for use with ALS patients but it has not been used as an endpoint in a clinical trial. 5 In contrast to PLACS, the Center for Neurologic Study-Lability Scale (CNS-LS) is a self- administered scale that has been validated in a large population of ALS patients. 6 It is short – seven items in the simplest iteration that chronicles labile tearfulness and laughter, and about twice that size when subscales measuring labile anger and frustration are included. (see Appendix 1 for the CNS-LS.) Since its publication in 1997, the CNS-LS has proven to be a useful diagnostic instrument and a robust clinical trial endpoint in ALS.7 While pseudobulbar affect commonly occurs in the setting of ALS, particularly in patients with bulbar involvement, it also occurs in a variety of other disorders including multiple sclerosis, Alzheimer’s disease, and stroke. The lack of disease specificity suggests a common anatomical substrate which in our opinion is best conceptualized as a disconnection syndrome. Several lines of evidence implicate brainstem and/or cerebellar connections to the cortex that are probably disrupted as a result of pathological processes. In the traditional view, advanced by Wilson in the 1920s, lesions in descending cortical pathways disrupt a brainstem control center that is hypothesized to reside in the upper pons or midbrain. This paradigm has been challenged by recent evidence suggesting that the cerebellum moderates emotional responses. Using advanced imaging techniques Parvizi et al. have reconstructed three-dimensional images of the brain of a patient with florid emotionality resulting from a cerebral vascular accident. 8 The only lesions seen in this patient were

Measuring pseudobulbar affect in ALS.

While the early diagnosis of disease is generally desirable, this is not always so. There is reason to be concerned about the reliability of clinical diagnosis of amyotrophic lateral sclerosis (ALS), based on currently available methods, early in the disease process. Applying the standard of cost-effectiveness it is possible to estimate the effort required to extend the lifespan of persons who are detected through a screening programme. Until it is possible to alter the treatment outcome, patients have little to gain by the early detection of ALS.

Effects of the early diagnosis of amyotrophic lateral sclerosis on the patient: disadvantages

Pharmaceutical compositions comprising dextromethorphan and quinidine in the treatment of neurological disorders

High-throughput screening of chemical libraries is traditionally utilized to identify potential drug candidates. A time-saving alternative to this resource-intensive process is to find new uses for existing drugs. The development of Nuedexta, a combination of dextromethorphan and quinidine, is an early example of this strategy. What initially began as a search for a drug that would inhibit excitotoxicity, thought to be an etiologic factor in stroke and neurodegenerative diseases, ultimately proved to be a potent symptomatic treatment for amyotrophic lateral sclerosis and kindred disorders. The basis for these unexpected results have led to renewed interest in the development of pharmacologic agents that target sigma receptors which preferentially decorate neurons in the brainstem and cerebellum. The story of Nuedexta, detailed herein, is a blueprint for drug discovery, complete with moments of inspiration and persistence in the face of doubt.

Repurposing FDA-approved pharmaceuticals: The development of Nuedexta

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