Jonathan S. Katz

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). Methods: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. Results: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. Recommendations: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B), and may be considered to slow the decline of forced vital capacity (Level C) and improve quality of life (Level C). Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).

Clinical spectrum of chronic acquired demyelinating polyneuropathies.

A number of presentations of chronic demyelinating polyneuropathy have been identified, each distinguished by its phenotypic pattern. In addition to classic chronic inflammatory demyelinating polyneuropathy (CIDP), which is characterized clinically by symmetric proximal and distal weakness and sensory loss, several regional variants can be recognized: multifocal motor neuropathy (MMN: asymmetric and pure motor), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (asymmetric, sensory, and motor), and distal acquired demyelinating symmetric (DADS) neuropathy (symmetric, distal, sensory, and motor). There are also temporal, pathological, and disease‐associated variants. This review describes a clinical scheme for approaching the chronic acquired demyelinating polyneuropathies that leads to a rational use of supportive laboratory studies and treatment options. In addition, we propose new diagnostic criteria for CIDP that more accurately reflect current clinical practice.

Distal acquired demyelinating symmetric neuropathy.

Objective: To characterize an acquired, symmetric, demyelinating neuropathic variant with distal sensory or sensorimotor features. Background: Classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients have prominent proximal and distal weakness. However, chronic demyelinating neuropathies may present with different phenotypes. An approach that distinguishes these disorders primarily according to the pattern of weakness may be useful to the clinician. Methods: A total of 53 patients with acquired symmetric demyelinating polyneuropathies were classified primarily according to the pattern of the neuropathy and secondarily according to the presence and type of monoclonal protein (M-protein) in this retrospective review. The authors distinguished between patients with distal sensory or sensorimotor involvement, designated as distal acquired demyelinating symmetric (DADS) neuropathy, from those with proximal and distal weakness, who were designated as CIDP. Results: M-proteins were present in 22% of patients with CIDP. There were no features that distinguished clearly between CIDP patients with or without an M-protein, and nearly all of these patients responded to immunomodulating therapy. In contrast, nearly two-thirds of the patients with DADS neuropathy had immunoglobulin M (IgM) kappa monoclonal gammopathies, and this specific combination predicted a poor response to immunomodulating therapy. Antimyelin-associated glycoprotein (anti-MAG) antibodies were present in 67% of these patients. Conclusion: Distinguishing acquired demyelinating neuropathies by phenotype can often predict the presence of IgM kappa M-proteins, anti-MAG antibodies, and responses to immunomodulating therapy.

Immune-mediated necrotizing myopathy associated with statins.

We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty‐five patients fulfilled our inclusion criteria. Twenty‐four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion‐body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune‐mediated etiology for this rare, statin‐associated necrotizing myopathy. Muscle Nerve, 2010

Multifocal acquired demyelinating sensory and motor neuropathy: The Lewis–Sumner syndrome

We report 11 patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, defined clinically by a multifocal pattern of motor and sensory loss, with nerve conduction studies showing conduction block and other features of demyelination. The clinical, laboratory, and histological features of these patients were contrasted with those of 16 patients with multifocal motor neuropathy (MMN). Eighty‐two percent of MADSAM neuropathy patients had elevated protein concentrations in the cerebrospinal fluid, compared with 9% of the MMN patients (P < 0.001). No MADSAM neuropathy patient had elevated anti‐GM1 antibody titers, compared with 56% of MMN patients (P < 0.01). In contrast to the subtle abnormalities described for MMN, MADSAM neuropathy patients had prominent demyelination on sensory nerve biopsies. Response to intravenous immunoglobulin treatment was similar in both groups (P = 1.0). Multifocal motor neuropathy patients typically do not respond to prednisone, but 3 of 6 MADSAM neuropathy patients improved with prednisone. MADSAM neuropathy more closely resembles chronic inflammatory demyelinating polyneuropathy and probably represents an asymmetrical variant. Given their different clinical patterns and responses to treatment, it is important to distinguish between MADSAM neuropathy and MMN.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III

Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.

Brachial amyotrophic diplegia: A slowly progressive motor neuron disorder

Objective: To describe a sporadic motor neuron disorder that remains largely restricted to the upper limbs over time. Background: Progressive amyotrophy that is isolated to the upper limbs in an adult often suggests ALS. The fact that weakness can remain largely confined to the arms for long periods of time in individuals presenting with this phenotype has not been emphasized. Methods: We reviewed the records of patients who had a neurogenic “man-in-the-barrel” phenotype documented by examination at least 18 months after onset. These patients had severe bilateral upper-extremity neurogenic atrophy that spared lower-extremity, respiratory, and bulbar musculature. Results: Nine of 10 patients meeting these criteria had a purely lower motor neuron disorder. During follow-up periods ranging from 3 to 11 years from onset, only three patients developed lower-extremity weakness, and none developed respiratory or bulbar dysfunction or lost the ability to ambulate. Conclusion: Patients presenting with severe weakness that is fully isolated to the upper limbs, without pyramidal signs, may have a relatively stable variant of motor neuron disease.

Electrophysiologic findings in multifocal motor neuropathy

Article abstract-We performed detailed electrophysiologic studies on 16 patients with clinically defined multifocal motor neuropathy and found a wide spectrum of demyelinating features. Only five patients (31%) had conduction block in one or more nerves. However, in 15 patients (94%) at least one nerve showed other features of demyelination. We also noted a significant degree of superimposed axonal degeneration in 15 patients. Eight patients (50%) had individual nerves with pure axonal injury, despite the presence of demyelinating features in other nerves. Antiganglioside antibodies were elevated in four of five patients with conduction block and five of 11 patients without conduction block. We conclude that multifocal motor neuropathy is characterized electrophysiologically by a wide spectrum of axonal and demyelinating features. Diagnostic criteria requiring conduction block may lead to underdiagnosis of this potentially treatable neuropathy. NEUROLOGY 1997;48: 700-707

Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. METHODS In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983. FINDINGS Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. INTERPRETATION Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. FUNDING Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.

Detecting frontotemporal dysfunction in ALS: Utility of the ALS Cognitive Behavioral Screen (ALS-CBS™)

Abstract Up to half of patients with ALS develop cognitive impairment during the course of the illness. Despite this, there is no simple tool for screening patients in the clinical setting. This study examines the sensitivity, specificity and accuracy of the ALS Cognitive Behavioral Screen (ALS-CBS™). We administered the measure to 112 ALS patients, including 31 who also underwent comprehensive neuropsychological testing. Screen results were validated by determining the accuracy against the full battery. Optimal cut-off scores for predicting the correct diagnosis were determined, and mean scores were compared between patients, controls and different diagnostic groups. The results demonstrated that mean cognitive scores differed between ALS and normal controls (p <0.0001). The cognitive section differentiated ALS-FTD from other ALS patients with 100% accuracy. Cognitively normal ALS patients could be distinguished from those with any cognitive deficit with 71% specificity and 85% sensitivity. A separate behavioral score was significantly lower in the ALS cohort compared to controls (p <0.0001) and predicted ALS-FTD with 80% sensitivity and 88% specificity. In conclusion, the ALS-CBS™ can aid in detecting cognitive and behavioral impairment in a clinical setting, although it does not replace formal diagnostic assessment. Further validation with larger sample sizes will clarify its clinical utility.