Hessel Franssen

A randomized sequential trial of creatine in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure. In a transgenic mouse model of ALS, creatine monohydrate showed a promising increase in survival. We performed a double‐blind, placebo‐controlled, sequential clinical trial to assess the effect of creatine monohydrate on survival and disease progression in patients with ALS. Between June 2000 and December 2001, 175 patients with probable, probable‐laboratory supported, or definite ALS were randomly assigned to receive either creatine monohydrate or placebo 10gm daily. A sequential trial design was used with death, persistent assisted ventilation, or tracheostomy as primary end points. Secondary outcome measurements were rate of decline of isometric arm muscle strength, forced vital capacity, functional status, and quality of life. The trial was stopped when the null hypothesis of indifference was accepted. Creatine did not affect survival (cumulative survival probability of 0.70 in the creatine group vs 0.68 in the placebo group at 12 months, and 0.52 in the creatine group vs 0.47 in the placebo group at 16 months), or the rate of decline of functional measurements. Creatine intake did not cause important adverse reactions. This placebo‐controlled trial did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with ALS. Ann Neurol 2003;53:437–445

Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study.

The effect of high dose intravenous immunoglobulin (IVIg) treatment was studied in six patients with multifocal motor neuropathy (MMN). All patients responded to treatment (0.4 g/kg for five consecutive days) in an open trial. The effect of IVIg treatment was confirmed for each patient in a single patient, double blind, placebo controlled trial. Four patients received two IVIg treatments and two placebo treatments, and two patients received one IVIg and one placebo treatment in a randomised order. Five out of six patients responded to IVIg but not to placebo. One patient responded to IVIg in the same manner as to placebo treatment. Thus IVIg treatment can lead to improvement of muscle strength in patients with MMN.

Ultrasonography shows extensive nerve enlargements in multifocal motor neuropathy

Using ultrasonography we found multiple sites with nerve enlargement along the course of the brachial plexus, median, ulnar, and radial nerves in the majority of 21 patients with multifocal motor neuropathy. Sonography and electrophysiologic studies showed more abnormalities than expected on purely clinical grounds. Moreover, sonography revealed nerve enlargement without clinical or electrophysiologic abnormalities.

Diagnostic value of high-resolution sonography in ulnar neuropathy at the elbow

Objective: To determine the diagnostic value of high-resolution sonography in ulnar neuropathy at the elbow (UNE). Methods: Sonographic ulnar nerve diameter measurement was compared at three levels around the medial epicondyle with a criterion standard including clinical and electrophysiologic characteristics in a cohort of 123 patients presenting with clinical signs of UNE. UNE or probable UNE was diagnosed in 84 patients and a different condition in 39 patient controls. Reference values were obtained in 56 healthy volunteers. Results: One hundred thirty-six affected arms were studied in 123 patients (UNE in 82, probable UNE in 9, and a different condition in 45 affected arms). Patients with UNE had a larger ulnar nerve diameter than patient controls (p < 0.0001). The sensitivity of sonography was 80%, specificity 91%, positive likelihood ratio 9, and negative likelihood ratio 0.2. The highest diagnostic yield was found in patients in whom electrodiagnostic studies showed signs of ulnar neuropathy but could not localize the lesion (17/20 cases, 86%) and in patients who had motor conduction velocity slowing across the elbow without conduction block (32/37 cases, 86%). Conclusions: High-resolution sonography is an accurate and easily applied test for the diagnosis of UNE. The authors recommend its use in addition to electrodiagnostic studies because it improves the reliability of the diagnosis of UNE.

Chronic idiopathic polyneuropathy presenting in middle or old age: a clinical and electrophysiological study of 75 patients.

The clinical and electrophysiological features were prospectively studied of 75 patients (46 men and 29 women) with chronic polyneuropathy presenting in middle or old age in whom a diagnosis could not be made even after extensive evaluation and a follow up of six months. The mean age at the onset of symptoms was 56.5 years. The clinical features of chronic idiopathic polyneuropathy are heterogeneous. On clinical grounds 44 patients had a sensorimotor, 29 patients a sensory, and two patients a motor polyneuropathy. The overall clinical course in chronic idiopathic polyneuropathy was slowly progressive. None of the patients became severely disabled. Electrophysiological and nerve biopsy studies were compatible with an axonal polyneuropathy. Antibodies against myelin associated glycoprotein, gangliosides, and sulphatides were assessed in 70 patients and found to be negative.

Multifocal motor neuropathy : Diagnostic criteria that predict the response to immunoglobulin treatment

As multifocal motor neuropathy (MMN) is a potentially treatable disorder, its differentiation from lower motor neuron disease is important. Evidence of conduction block (CB) is considered one of the relevant criteria for the diagnosis of MMN. Strict criteria for CB may lead to underdiagnosis of MMN, however. Using a standardized examination, we studied the clinical, laboratory, and electrophysiological characteristics of 37 patients presenting with a lower motor neuron disorder and electrophysiological features compatible with segmental demyelination. We propose a set of clinical, laboratory, and electrophysiological criteria for the diagnosis of MMN, which has been verified by follow‐up and response to treatment with intravenous immunoglobulins. Based on the clinical, laboratory, and electrodiagnostic features, 21 patients were diagnosed with definite MMN (17 responders), 7 were diagnosed with probable MMN (5 responders), and 9 were diagnosed with possible MMN (1 responder). Age at onset, the number of affected limb regions, and the number of patients with a creatine kinase level greater than 180 U/L were significantly lower in responders than in nonresponders. Elevated anti‐GM1 antibodies and definite CB were found significantly more often in responders. The proposed diagnostic criteria may be useful in clinical practice and therapeutic trials. Ann Neurol 2000;48:919–926

Magnetic resonance imaging of the brachial plexus in patients with multifocal motor neuropathy

We studied whether magnetic resonance (MR) imaging of the brachial plexus is useful to distinguish multifocal motor neuropathy (MMN) from lower motor neuron disease (LMND) and whether abnormalities resemble those of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We compared MR images of the brachial plexus of nine patients with MMN with scans from five patients with CIDP, eight patients with LMND, and 174 controls. In two patients with MMN, and in three patients with CIDP, the MR images showed an increased signal intensity on the T2-weighted images of the brachial plexus. Two other patients with MMN demonstrated a more focal, increased signal intensity on the T2-weighted images, occurring in one patient only in the axilla, and in the other patient in the axilla and in the ventral rami of the roots. MR images of the brachial plexus of eight patients with LMND were normal. The distribution of the MR imaging abnormalities corresponded with the distribution of symptoms of the patients: asymmetrical in MMN and symmetrical in CIDP. These findings demonstrate that MR imaging abnormalities of the brachial plexus in patients with MMN resemble those seen in CIDP and may be useful to distinguish MMN from LMND.

Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies.

Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.

Intermittent cyclophosphamide and prednisone treatment of polyneuropathy associated with monoclonal gammopathy of undetermined significance

In an open prospective study, we analyzed the effect of cyclophosphamide (300 mg/m2 body surface daily for 4 days) combined with prednisone (40 mg/m2 body surface daily for 5 days) at 4-week intervals during 6 months in 16 patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS). Eleven patients had an IgM-MGUS and five an IgG-MGUS. During a follow-up period of 3 years, eight patients had improvement and six patients stabilized, based on quantitative neurologic examination, the Rankin disability scale, and electrophysiologic studies. These 14 patients had neuropathy with demyelinating and axonal features. One patient with a purely axonal neuropathy had deterioration despite therapy. One other patient developed severe leukopenia as side effect of cyclophosphamide, necessitating withdrawal of treatment. A difference in response was not present in patients with IgM- or IgG-MGUS, nor in patients with or without autoantibodies against myelin-associated glycoprotein. Nine patients had a bone marrow biopsy before and 1 year after treatment. In eight patients, the monoclonal lymphoid IgM or plasma cell IgG infiltration decreased, while in four the monoclonality disappeared after treatment. In the patient who had neurologic deterioration, repeated bone marrow biopsy showed deposits of amyloid. In conclusion, short-term treatment with intermittent cyclophosphamide and prednisone may have a long-term favorable effect in patients with demyelinating polyneuropathy associated with MGUS. NEUROLOGY 1996;47: 1227-1233

Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy

Reply from the Authors: We thank Dr. Nabbout et al. for their comments on our article, in which we described 13 probands, and one of their mothers, with epilepsy variably associated with mental retardation and autistic features in whom the PCDH19 gene was mutated.1 The epilepsy phenotype was variable. Seven patients exhibited DS and 6 had focal epilepsy. These figures confirm that PCDH19 mutations can cause an epileptic encephalopathy resembling DS in girls.2 Therefore, if screening for SCN1A gene mutations, deletions, amplification, or duplications yields negative results, PCDH19 should be screened. In our cohort, girls with PCDH19 mutations and focal epilepsy had early seizure onset and either normal cognitive skills or mental retardation and autistic features. The spectrum of phenotypes associated with PCDH19 mutations is broad, ranging from mild epilepsy to a severe epileptic encephalopathy. Such phenotypic diversity might be partially explained by the cosegregation of other genetic factors either rescuing or worsening the phenotype. Since our article was accepted for publication, we have observed 6 more girls with PCDH19 mutations, none having a phenotype evocative of DS (unpublished data). Another article reported 3 girls with seizure onset in infancy and varying degrees of cognitive impairment and autistic features.3 However, the core clinical features of PCDH19-related epilepsy phenotypes seem to be early onset of seizures occurring in clusters and precipitated by fever. The spectrum of associated cognitive and behavioral impairment is variable and its relationship with epilepsy severity is not obvious. PCDH19 is clearly emerging as a major epilepsy gene in females. Analysis of larger cohorts, with unbiased recruitment, will clarify the full range of phenotypes caused by alterations in this gene.