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- portedP 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-

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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 OF CLINICAL PHENOTYPES Patients were classified at baseline and reclassified at the end Follow-up was 18 months since we expected that patients with of follow-up into the following clinical phenotypes: patients PMA, with a rate of progression comparable with that ob- with generalized SMA in whom more than 50% of the limb reserved in ALS, would clearly deteriorate during that period. Pa- gions were affected and patients with nongeneralized weak- tients had assessments every 3 months, including a standard- ness (Յ50% affected limb regions), consisting of individuals ized history and assessment of muscle strength, muscle atrophy, with distal symmetrical weakness in the legs and/or arms (dis- reflexes, VC, and functional impairment. Each patient was in- tal SMA) and individuals with mainly asymmetrical weakness vestigated by the same assessor (J.V. or R.M.VdB-V.). Prior to in the arms or legs (segmental SMA). the study, examiners practiced performing and interpreting reflexes in a standardized manner to minimize interobserver bias. Muscle strength was scored with the modified 9-grade scale SURVIVAL of the Medical Research Council (MRC).20,21 Table 1 shows the measured muscle groups. The MRC sum score, which is We hypothesized that most of our patients with PMA would the sum of the MRC scores of 42 measured muscle groups, was have a fast disease progression like in ALS, and therefore, we calculated at each visit (MRC 5=5.00; MRC 5−=4.67; MRC decided to perform a survival analysis 5 years after the last pa- 4ϩ=4.33; MRC 4=4.00; MRC 4−=3.67; MRC 3=3.00; MRC tient’s end of follow-up. We contacted the patient’s general phy- 2=2.00; MRC 1=1.00; MRC 0=0.00; maximum score, 210).21 sician to obtain information on the date and cause of death.

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Characteristic Sample Size 6 Male/female 25/12 Disease duration, mo, 19 (5-48) median (range) 5 Age at onset of weakness, y, 57 (25-72) median (range) Site of onset 4 Limb/bulbar 36/0 Respiratory muscles 1 Arms/legs 20/16 Mean No. of Affected Regions 3 Distal/proximal 27/9

2 0 3 6 9 12 15 18 Baseline Last Visit Months Since Inclusion Disease severity, median (range) B Affected limb regions 4 (1-8) 6 (1-8) 190 (maximum 8) ALSFRS score (maximum 40) 33 (17-38) 23 (9-38) MRC sum score (maximum 180.5 (65.6-206.3) 142.9 (32.3-204.3) 180 210) Clinical phenotype, No. (%) Generalized spinal muscular 25 (68) 32 (86) 170 atrophy Segmental spinal muscular 8 (21) 2 (6) atrophy 160 Distal spinal muscular 4 (1) 3 (8) atrophy Mean MRC SUM Score Classification according to El 150 Escorial criteria, No. Suspected ALS 37 25 Possible ALS 6 140 0 3 6 9 12 15 18 Probable ALS 6 Months Since Inclusion

Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS, Amyotrophic C Lateral Sclerosis Functional Rating Scale; MRC, Medical Research Council. 36

32 STATISTICAL ANALYSIS 30

Patient characteristics were analyzed using descriptive statis- 28 tics. To examine the disease progression of PMA, as expressed by the MRC sum score, the number of affected regions, and the 26 ALSFRS score, a linear mixed-effects model (repeated mea- Mean ALSFRS Score surements) was used. The impact of the potential prognostic 24 factors on each outcome measure of disease progression was 22 additionally analyzed using multivariate linear regression. Sta- tistics were expressed in standardized regression coefficients 20 2 0 3 6 9 12 15 18 and total variance, explained (R ). In case no complete patient Months Since Inclusion data set could be obtained, we analyzed the data by the last ob- servation carried forward approach. Patient survivals were presented by Kaplan-Meier curves (censoring date, June 19, 2006). Figure 1. Graphs showing the repeated measurement analysis on the 3 outcome scores for all patients. Point estimates with 95% confidence In conformity with ALS studies, we chose the date of initial weak- intervals are given. A, Mean number of affected limb regions. B, Mean Medical ness as the start of the survival time observed. Research Council (MRC) sum score. C, Mean Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score. RESULTS phone. Therefore, a complete data set was obtained for After screening approximately 600 potential eligible pa- 28 patients, and 32 patients had a complete ALSFRS score. tients, 37 patients met our inclusion criteria. Their char- For all patients, survival data were available. acteristics and clinical phenotypes are presented in Table 2. No patients had a bulbar onset. In 9 patients, PROGRESSION OF DISEASE OVER TIME follow-up was not completed to the end of the study because of physical inability to visit our clinic. In 4 of them, Figure 1 shows the progression of disease as expressed by follow-up to the end of the study was done by tele- the 3 outcome scores. On average, muscle strength decreased

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 by mean 6.01 MRC sum score points (95% confidence interval [CI], 3.84-8.18) (P value Ͻ.001), and the number of Table 3. Effects of Prognostic Variables on Outcome affected regions increased by mean 0.53 per 3 months (95% Measures of PMA Progression CI,0.42-0.65)(PvalueϽ.001).Patientfunctioningdecreased Outcome Measures of PSMA by mean 1.85 ALSFRS score points per 3 months (95% CI, Progression ␤ Coefficients* 1.38-2.33) (Pvalue Ͻ.001). After a follow-up of 18 months, 8patients(22%)haddied.Alldiedofrespiratorymuscleweak- ALSFRS MRC Sum No. of Affected ness (with or without pneumonia). Score Score Regions VC at baseline 0.320 ...... PROGNOSTIC FACTORS Decrease in VC 0-6 mo 0.511 . . . −0.400 Age at onset . . . 0.431 . . . Total R 2,† % 42 19 38 Univariate analysis showed that all the prognostic factors were significantly associated with each of the outcome mea- Abbreviations: ALSFRS, Amyotrophic Lateral Sclerosis Functional Rating sures (data not shown). Multivariate analysis (Table 3) Scale; MRC, Medical Research Council; PMA, progressive muscular atrophy; showed that VC at baseline was a significant prognostic fac- PSMA, progressive spinal muscular atrophy; VC, vital capacity. *␤ Coefficients are standardized regression coefficients. tor of PMA progression as measured by the ALSFRS score. †R 2 is the percentage of the total variation of the dependent variable score Decrease of VC during the first 6 months of the study was that is explained by the independent variables together. a significant prognostic factor as measured by the ALSFRS score and the number of affected regions. Age at onset was a prognostic factor as measured by the MRC sum score, im- SURVIVAL plying that PMA progression was faster in younger patients. Five years after the end of the study, median 7 years af- CLINICAL FEATURES AND EVALUATION ter inclusion (range, 76-95 months), 11 patients were alive OF CLINICAL PHENOTYPES (Table 4). Figure 2 shows the Kaplan-Meier survival curve for the 37 patients with PMA. Calculated from the UMN Signs time of initial weakness, the 1-, 3-, 5-, and 9-year survival rates were 100%, 67%, 45%, and 30%, respec- During follow-up, UMN signs appeared in 13 patients tively, with a median survival duration of 56 months. All (Table 4). Two of 13 patients had pseudobulbar signs the patients with bulbar signs at inclusion died, with a (forced laughter, crying, or yawning), with no addi- median survival from the date of inclusion of 17.5 months tional UMN signs on examination. Both had general- (range, 4.6-35.4 months). Calculated from the time of ized SMA at inclusion. Four of 13 patients developed ex- initial weakness, median survival in all these patients was tensor plantar response. Three of them were initially 38.1 months (range, 12.7-55.4 months). classified as having generalized SMA and also demon- Four of our patients received noninvasive respira- strated other UMN signs (clonic reflex, hyperreflexia in tory aids as a life-prolonging measure: 1 patient used noc- a weak and wasted muscle, Hoffmann sign) in 1 or more turnal bilevel positive airway pressure and 3 patients used limbs. One patient, initially classified as having distal SMA, intermittent positive-pressure ventilation. One patient developed no other UMN signs. He progressed to gen- used tracheostomy, intermittent positive-pressure ven- eralized SMA during follow-up. Seven of 13 patients de- tilation until death. veloped hyperreflexia in a weak and wasted muscle in 1 or more limbs during follow-up. Three of these 7 also developed a Hoffmann sign. Six of 7 had generalized SMA COMMENT at inclusion. The patient with initial segmental SMA progressed to generalized SMA during follow-up. Our prospective study on 37 patients with well-defined PMA who were followed up from early on in the disease Bulbar Signs course demonstrated that the prognosis in PMA is al- most as poor as in ALS.24-27 Nearly all our patients dem- None of our patients had a bulbar onset. At inclusion, onstrated relentless disease progression, leading to death 10 of 37 patients were found to have bulbar signs. An- in 8 patients and to rapid spread of weakness in 24 other other 6 patients developed bulbar signs during follow- patients within 18 months. Five years after the end of the up. Of the 16 patients who eventually developed bulbar study, 26 patients (70%) had died. However, the mor- signs, 13 had early respiratory symptoms, 8 developed tality probabilities presented may be an underestimate UMN involvement, and 15 died less than 5 years after because of the possible selection bias of patients with PMA onset of weakness (Table 4). In contrast, of the 21 pa- who had died before potential inclusion into our study. tients without bulbar symptoms, only 4 developed res- Five of our patients with either distal symmetrical or piratory symptoms, 7 developed UMN involvement, and asymmetrical unilateral muscle weakness had a (nearly) 5 died less than 5 years after onset of weakness. static disease course, which supports the hypothesis that patients with various diseases may fulfill our inclusion Classification of Clinical Phenotypes criteria for PMA, especially early on in the disease course. The distribution of weakness in 3 of the 4 patients with The classification of the phenotypes at baseline and at a phenotype of symmetrical distal weakness in the ex- 18 months of all patients is presented in Table 4. tremities remained unchanged during follow-up. There-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 4. Classification and Characteristics of Phenotypes at Baseline and at 18 Months of All Patients

Patient No./ Disease Phenotype Phenotype Early Respiratory Bulbar UMN Sex/Age, y Duration, mo at Onset* at 18 mo* Symptoms Symptoms Signs Deceased? 1/M/52 39 Segmental Segmental No No No No 2/F/59 36 Segmental Segmental No No No No 3/F/56 32 Segmental Generalized No No No No 4/M/62 14 Segmental Generalized No No No Yes, 71 mo 5/M/61 17 Segmental Generalized No No No Yes, 38 mo 6/F/37 12 Segmental Generalized Yes Yes No Yes, 18 mo 7/M/62 19 Segmental Generalized Yes Yes No Yes, 22 mo 8/M/53 6 Segmental Generalized Yes No Yes Yes, 34 mo 9/M/56 30 Distal Distal No No No No 10/M/44 33 Distal Distal No No No No 11/M/53 30 Distal Distal No No No No 12/M/51 27 Distal Generalized Yes No Yes Yes, 87 mo 13/F/66 48 Generalized Generalized No No No No 14/M/61 48 Generalized Generalized No No No Yes, 90 mo 15/F/69 48 Generalized Generalized No No No Yes, 108 mo 16/F/54 48 Generalized Generalized No No No Yes, 107 mo 17/M/66 19 Generalized Generalized No No Yes No 18/F/67 48 Generalized Generalized No No Yes No 19/M/63 30 Generalized Generalized No No Yes No 20/F/63 20 Generalized Generalized No No Yes Yes, 56 mo 21/M/53 28 Generalized Generalized No No Yes Yes, 74 mo 22/M/54 17 Generalized Generalized No Yes No Yes, 52 mo 23/M/56 42 Generalized Generalized No Yes Yes Yes, 48 mo 24/F/53 17 Generalized Generalized No Yes Yes Yes, 31 mo 25/M/51 16 Generalized Generalized Yes No No Yes, 30 mo 26/M/46 5 Generalized Generalized Yes No No Yes, 31 mo 27/M/56 18 Generalized Generalized Yes Yes No No 28/M/24 19 Generalized Generalized Yes Yes No Yes, 27 mo 29/M/48 36 Generalized Generalized Yes Yes No Yes, 53 mo 30/M/42 33 Generalized Generalized Yes Yes No Yes, 51 mo 31/M/65 8 Generalized Generalized Yes Yes No Yes, 13 mo 32/M/70 6 Generalized Generalized Yes Yes Yes Yes, 25 mo 33/F/68 12 Generalized Generalized Yes Yes Yes Yes, 42 mo 34/F/46 17 Generalized Generalized Yes Yes Yes Yes, 56 mo 35/M/64 14 Generalized Generalized Yes Yes Yes Yes, 25 mo 36/F/59 6 Generalized Generalized Yes Yes Yes Yes, 28 mo 37/M/49 18 Generalized Generalized Yes Yes Yes Yes, 34 mo

Abbreviation: UMN, upper motor neuron. *“Generalized” indicates more than 50% of the limb regions affected; “distal,” distal symmetrical weakness in legs and/or arms; and “segmental,” asymmetrical weakness in arms or legs.

fore, we classified them as having (hereditary or spo- Our study showed a significant decline of muscle radic) distal SMA.19 Two patients with PMA with a strength and a significant increase in the number of af- phenotype of segmental asymmetrical weakness re- fected limb regions and functional impairment as mea- stricted to the hand and forearm showed no progression sured by the ALSFRS score. Predictors for an unfavor- during follow-up. This relatively good prognosis is in able outcome were VC at baseline lower than 90% of the agreement with previous studies reporting on this phe- predicted value, decline in VC in the first 6 months, and notype.19,28,29 On the other hand, 6 of 8 patients with this a younger age at onset. This latter association is remark- segmental phenotype evolved into the phenotype of gen- able since numerous studies in ALS demonstrated the op- eralized PMA or ALS within 18 months. Two of them had posite; older patients tended to show faster disease pro- predominant proximal arm weakness at inclusion. This gression.7,9,33 Subsequently, a repeat analysis after removal is in contrast to previous studies reporting a benign prog- of 3 outliers who were all young and demonstrated rapid nosis of patients with proximal segmental SMA,19 also progression showed no significant effect of age at onset. known as the flail arm syndrome.30-32 Although unique Therefore, the finding that a younger age at onset was cases with a more benign prognosis exist, data in these associated with a worse prognosis may simply reflect the studies were collected retrospectively, which may have relatively small sample size, which allowed for 3 young led to selection bias. Although none of our patients had patients with rapid disease progression to skew the over- a bulbar onset, we noted that 15 of the 16 patients who all results. eventually showed bulbar features developed either ALS As in ALS, the results of our study support the hy- or had an ALS-like disease course. pothesis that there is a strong relation between respira-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 sembles the reported rate of 50% in ALS.25 These find- 1.2 ings suggest that PMA and ALS are variants of a clinical spectrum, which varies from purely LMN or UMN involvement to the classic condition ALS with a combina- 34 1.0 tion of UMN and LMN signs. According to the 1994 El Escorial criteria, patients with PMA were included in the category “suspected ALS.” However, in the 1998 revised El Escorial criteria, this sub- 0.8 group was omitted4,13 because a pure LMN syndrome was not regarded sufficiently certain for the diagnosis of ALS. As a consequence, patients with PMA are not included 0.6 in ALS research studies. However, our data showed that Cumulative Survival most patients with PMA have a relentlessly progressive disease course as in ALS. This poor prognosis is deter-

0.4 mined by VC at baseline lower than 90% of predicted value Survival or with declining VC during the first 6 months. There- Function fore, we recommend that patients with early PMA who Censored meet at least 1 of these 2 criteria may also benefit from 0.2 0 20 40 60 80 100 120 140 possible new treatment forms developed for ALS. Time Since First Weakness, mo Accepted for Publication: November 21, 2006. Figure 2. Kaplan-Meier curve for the whole group. Correspondence: Jeldican Visser, MD, Department of Neurology (H2-235), Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands (j.visser tory function parameters and outcome in PMA. In our @amc.uva.nl). study, the most powerful predictor of rapid progression Author Contributions: Dr Visser had full access to all of was decline in VC in the first 6 months. The effect of this the data in the study and takes responsibility for the in- predictor on the ALSFRS score may be explained by the tegrity of the data and the accuracy of the data analysis. item “breathing” of the ALSFRS score. However, de- Study concept and design: Visser, van den Berg-Vos, cline in VC was also an independent predictor of out- Franssen, van den Berg, Wokke, de Jong, de Haan, and come when measured by the number of affected re- de Visser. Acquisition of data: Visser, van den Berg-Vos, gions. In addition, we found an independent unfavorable Franssen, Wokke, and de Jong. Analysis and interpreta- effect of low VC at baseline on outcome in our patients. tion of data: Visser, van den Berg-Vos, van den Berg, The relatively small sample size of our study does not Holman, de Haan, and de Visser. Drafting of the manu- allow for more precise predictions of prognosis in indi- script: Visser, van den Berg-Vos, Wokke, and de Visser. vidual cases. Thus, evaluation of respiratory function is Critical revision of the manuscript for important intellec- needed soon after a patient is diagnosed with PMA. If ini- tual content: van den Berg-Vos, Franssen, van den Berg, tial VC is lower than predicted, this patient should be Wokke, de Jong, Holman, de Haan, and de Visser. Sta- followed up with extra caution. If pulmonary function tistical analysis: Holman and de Haan. Obtained funding: further declines during the following 6 months or the pa- van den Berg and de Visser. Administrative, technical, and tient develops bulbar signs and/or generalization of weak- material support: Visser and Franssen. Study supervision: ness, a poor prognosis is very likely. van den Berg, Wokke, de Jong, de Haan, and de Visser. Vital capacity at baseline or change in VC did not show Financial Disclosure: None reported. a significant effect on the MRC sum score. For the 9 pa- Funding/Support: This work was supported by a grant tients with incomplete data sets, last observations were from the Prinses Beatrix Fonds, The Hague, and the Amyo- carried forward. Therefore, their MRC sum scores pos- trophic Lateral Sclerosis Research Fund, Netherlands sibly underestimate disease severity at the end of follow- Foundation, Enschede, the Netherlands. up, in contrast to the ALSFRS score, for which we obtained a complete data set in 4 of these 9 patients. REFERENCES Although none of our patients had a bulbar onset, 10 patients (27%) demonstrated bulbar symptoms at inclu- 1. Aran FA. Recherches sur une maladie non encore de´crite du système musculaire sion. The notion in earlier reports that bulbar motor neu- (atrophie musculaire progressive). Arch Ge´ne´rales de Me´decine. 1850;24:5-35. rons are rarely affected in PMA3 might be true for pa- 2. Muller R. Progressive motor neuron disease in adults. Acta Psychiatr Neurol Scand. tients with a slowly progressive form of SMA only. 1952;27:137-156. Clear UMN signs were detected in 13 patients during 3. Norris FH. Adult progressive muscular atrophy and hereditary spinal muscular atrophies. In: Vinken PJ, Bruyn GW, Klawans HL, de Jong JMBV, eds. Hand- follow-up, whose diagnosis at that time had to be changed book of Clinical Neurology. Amsterdam, the Netherlands: Elsevier Science; 1991: to ALS, albeit with a PMA-like onset. Other patients with 13-26. PMA showed a rapidly progressive disease course like in 4. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O. Clinical features of ALS but without developing UMN signs (or detection of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria. Arch Neurol. 2000;57:1171-1176. UMN involvement may not be feasible in a patient with 5. Brownell B, Oppenheimer DR, Hughes JT. The central nervous system in motor predominantly LMN features). Moreover, the 3-year mor- neurone disease. J Neurol Neurosurg Psychiatry. 1970;33:338-357. tality rate of 33% in our patients with PMA closely re- 6. Ince PG, Evans J, Knopp M, Forster G, Hamdalla HHM, Wharton SB. Corticospi-

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