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Disease Course and Prognostic Factors of Progressive Muscular Atrophy

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Disease Course and Prognostic Factors of Progressive Muscular Atrophy ORIGINAL CONTRIBUTION Disease Course and Prognostic Factors of Progressive Muscular Atrophy Jeldican Visser, MD; Renske M. van den Berg-Vos, MD, PhD; Hessel Franssen, MD, PhD; Leonard H. van den Berg, MD, PhD; John H. Wokke, MD, PhD; J. M. Vianney de Jong, MD, PhD; Rebecca Holman, PhD; Rob J. de Haan, PhD; Marianne de Visser, MD, PhD Objective: To investigate the natural history and prog- Results: Significant decline of muscle strength (mean, nostic factors in patients with nonhereditary, adult- 6.01 Medical Research Council sum score points [95% onset progressive muscular atrophy. confidence interval [CI], 3.84-8.18]; P value Ͻ.001) and significant increase in the number of affected regions Design: Inception cohort conducted for 18 months. (mean, 0.53 affected region [95% CI, 0.42-0.65]; P value Settings: Three university hospitals in the Nether- Ͻ.001) and functional impairment (mean, 1.85 Amyo- lands (referral centers for neuromuscular diseases). trophic Lateral Sclerosis Functional Rating Scale score points [95% CI, 1.38-2.33]; P value Ͻ.001) were found. Patients: Thirty-seven consecutive patients newly di- Ͻ Vital capacity (VC) at baseline and decrease of VC dur- agnosed (onset of weakness 4 years) with progressive ing the first 6 months were significantly associated with muscular atrophy enrolled between 1998 and 2001. outcome. Median survival duration after initial weak- Main Outcome Measures: Disease progression was mea- ness was 56 months. sured at 0, 3, 6, 9, 12, 15, and 18 months by the Medical Research Council sum score, number of affected limb re- Conclusions: This study shows that patients with progres- gions, and the Amyotrophic Lateral Sclerosis Functional sive muscular atrophy have a relentlessly progressive dis- Rating Scale score. Multivariate linear regression analysis ease course. Patients with a low VC at baseline and a sharp was used to identify predictors of poor outcome. Clinical decline of VC during the first 6 months have an especially features and classification of phenotype during follow-up poor prognosis. were evaluated. Survival analysis was planned after data col- lection, performed 5 years after the end of the study. Arch Neurol. 2007;64:522-528 ROGRESSIVE SPINAL MUSCULAR Studies of ALS show that age at onset atrophyisanadult-onset,non- beyond 55 years, bulbar onset, respira- hereditary progressive disease tory vital capacity (VC) lower than 60% of the lower motor neurons of the predicted value, and rapid decline (LMNs).In1850,Aran1 firstre- in pulmonary function are unfavorable pre- Pported this disease, which he called progres- dictors of prognosis and survival.7-10 Re- sive muscular atrophy (PMA). In 1952, ports on the natural course of nonheredi- Muller2 introduced the term progressive spi- tary PMA are sparse. Interpretation of these nal muscular atrophy, since then synony- studies is hampered because of the retro- mouslyusedwithPMA.Inthisarticle,weuse spective design of these studies, hetero- thetermprogressivemuscularatrophy(PMA) geneous patient groups, and lack of stan- to differentiate it from the familial form of dardized neurological assessment.2,11,12 Author Affiliations: spinal muscular atrophy (SMA). Herein, we present the results of our Departments of Neurology 1 study of 18 months of disease course and (Drs Visser, de Jong, and The patients reported by Aran and Muller2 had muscle wasting and weakness its prognostic factors in patients with PMA de Visser) and Clinical with a short disease duration. In addition, Epidemiology and Biostatistics with slow progression over years to de- (Drs Holman and de Haan), cades.3 A proportion of these patients de- we have calculated the survival rate 5 years Academic Medical Center, veloped amyotrophic lateral sclerosis (ALS) after the last patient’s end of follow-up. University of Amsterdam, in due course, manifesting with rapidly pro- Amsterdam, the Netherlands; gressive muscle weakness and appearance METHODS Departments of Neurology of upper motor neuron (UMN) signs.4 In au- (Drs van den Berg-Vos, topsy series, corticospinal tract involve- van den Berg, and Wokke) and PATIENTS Clinical Neurophysiology ment was demonstrated in 50% of patients 5,6 (Dr Franssen), University with nonhereditary PMA. Therefore, PMA Between 1998 and 2001, consecutive patients Medical Center Utrecht, is regarded as a heterogeneous syndrome newly diagnosed with PMA in 3 university hos- Utrecht, the Netherlands. showing considerable overlap with ALS. pitals in the Netherlands were asked to partici- (REPRINTED) ARCH NEUROL / VOL 64, APR 2007 WWW.ARCHNEUROL.COM 522 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Categorization of Muscle Groups per Limb Region Region Muscle Groups Myotomes Upper cervical region Shoulder abduction, elbow flexion, elbow extension C5-C7 Lower cervical region Wrist flexion, wrist extension, extension of fingers, flexion of fingers, spreading of fingers, abduction C8-Th1 of thumb, adduction of thumb, and opposition of thumb Upper lumbosacral region Hip flexion, hip adduction, knee extension, hip extension, hip abduction L1-L3 Lower lumbosacral region Knee flexion, plantar flexion of foot, flexion of toes, dorsiflexion of foot, extension of toes L4-S1 pate in the study. All patients underwent a standardized neurologi- We pooled the separate muscles in 8 limb regions (Table 1). cal, laboratory, and electrophysiological examination. We considered a limb region affected when 1 or more muscle Inclusion criteria were age at onset older than 18 years, disease groups per region had an MRC score of MRC 4ϩ or less. We duration of less than 4 years from the time of onset of weakness, recorded the number of affected limb regions at each visit. and clinical and electrophysiological evidence of progressive LMN Muscle atrophy was determined in muscle groups and limb involvement (weakness, atrophy, and fasciculation) in 1 or more regions. Biceps, triceps, and knee and ankle reflexes were scored of 4 regions (bulbar, cervical, thoracic, and lumbosacral) accord- according to the National Institute of Neurological Disorders ing to the 1998 revised El Escorial criteria.13 The span of 4 years and Stroke myotatic reflex scale.22 was short enough for relatively early inclusion but also long enough Slow respiratory VC was measured and expressed as a per- for inclusion of a sufficient number of patients. Exclusion criteria centage of the predicted value. Functional impairment was evalu- includedmotorconductionblock(s)onextensivestandardizednerve ated with the ALS Functional Rating Scale (ALSFRS), which is conductionstudiesaccordingtopreviouslydefinedcriteria,14,15 defi- a 10-item scale that rates the function on activities of daily liv- nite clinical UMN signs (pseudobulbar symptoms, including forced ing (best score is 40, worst score is 0).23 laughter,yawning,andcrying;clonusofmasseterreflex;(sub)clonic To document the progression of PMA, we used the MRC sum myotatic reflexes; extensor plantar response; and spasticity), ob- score, the number of affected limb regions, and the ALSFRS score jective sensory signs (apart from mild vibration sense disturbances at each visit as outcome measures. We documented the develop- in elderly patients), history of diseases that may mimic motor neu- ment of clinical UMN signs during follow-up. We looked for pseu- ron disease (ie, spinal radiculopathy, poliomyelitis, and diabetic dobulbar symptoms (forced laughter, yawning, and crying), amyotrophy), family history of inherited SMA, and deletion in the clonus of masseter reflex, (sub)clonic myotatic reflexes, extensor SMN1 gene or an expansion of CAG repeats (Ͼ40) in the andro- plantar response, hyperreflexia in a weak, wasted muscle, and posi- gen receptor gene.16,17 tive Hoffmann sign. Retained reflex in a weak, wasted muscle is Laboratory tests included erythrocyte sedimentation rate and defined as hyperreflexia (score 3 on the National Institute of Neu- levels of hemoglobin, hematocrit, thyrotropin, serum protein rological Disorders and Stroke myotatic reflex scale)22 in combi- electrophoresis and serum immunoelectrophoresis with im- nation with frank atrophy and weakness rated as an MRC score munofixation, phosphate, calcium (and, if elevated, parathy- of MRC 4 or less. We documented the development of bulbar signs roid hormone), and serum IgM anti-GM1 antibodies. Neuro- during follow-up (ie, tongue atrophy with or without fascicula- imaging studies ruled out structural lesions (tumors, tions and diminished tongue strength, dysarthria, or dysphagia). intervertebral disk herniation, vascular lesions, and syringo- myelia) of the spinal cord or craniocervical junction. PROGNOSTIC FACTORS The electrophysiological investigation took place after warm- ing the limbs, as described elsewhere.18 Extensive standard- Based on the results from previous studies in ALS,7-10 we chose ized nerve conduction studies and concentric needle electro- the following 4 potential prognostic factors: age at onset, VC myography were conducted by the same investigator (H.F.) in at baseline, difference in VC between baseline and 6 months, all patients, according to a standardized protocol.14,19 and site of onset (arm or leg), the latter because of the sup- The study was approved by the local medical ethics com- posed earlier involvement of respiratory muscles in patients with mittees and written informed consent was obtained from all par- arm-weakness onset compared with patients with leg onset. ticipants. ASSESSMENTS CLASSIFICATION
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