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Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis
Clinical Neurology and Neurosurgery 112 (2010) 103–105
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis夽 Markus Kraemer ∗ , Melanie Buerger, Peter Berlit Department of Neurology, Alfried Krupp von Bohlen und Halbach Hospital, Alfried-Krupp-Strasse 21, 45117 Essen, Germany
a r t i c l e
i n f o
Article history: Received 30 January 2009 Received in revised form 15 August 2009 Accepted 3 October 2009
Keywords: Amyotrophic lateral sclerosis Delay of diagnosis Diagnostic problems Inappropriate surgery Time to diagnosis
a b s t r a c t Objective: Initial symptoms of amyotrophic lateral sclerosis (ALS) mimic several neurological syndromes that may decelerate a correct diagnosis. The aim of our study was to investigate if diagnostic and therapeutic parameters have influence on the time of diagnosis. Methods: We retrospectively reviewed the medical records of 100 consecutive ALS patients focusing on clinical and diagnostic data, the timing of diagnosis and treatments attributed to the onset of symptoms of ALS. Results: Among 100 consecutive patients with ALS, 12% underwent surgery due to symptoms retrospectively attributable to ALS. The comparison of duration from first symptoms to correct diagnosis showed a significant difference between operated and non-operated patients. 35% of all ALS patients had bulbar onset symptoms. The mean time from first symptoms to diagnosis was 9 months in this group. In patients without bulbar onset it was 16.4 months which also represents a significant difference. In 44% of patients other diagnoses were considered and medically treated previous to correct diagnosis, but there was no significant delay of diagnosis. Conclusion: Our study confirms that diagnosis of ALS is still a common clinical problem and shows the need of sensitive and specific diagnostic tests. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Amyotrophic lateral sclerosis (ALS), a progressive and fatal disease with degeneration of motor neurons in the brain and the spinal cord, was described in 1881 by the French neurologist Jean-Martin Charcot. It is generally felt that the clinical picture of ALS is easy to recognise in its fully developed form [1]. In 1990, international experts for ALS met in a Spanish palace-monastery, El Escorial. The resulting consensus document on ALS diagnostic criteria was published in its final version in 1994 [2,3]. The El Escorial, the revised Airlie House and the Awaji diagnostic criteria for ALS were introduced to select patients for clinical trials [4–10]. However several variations early in the course of ALS make the diagnosis more challenging and allow for the possibility of an alternative, incorrect diagnosis [1]. There might be various reasons diagnosis may be delayed, including the perception of people that it is a desirable character trait to delay seeking help for vague symptoms and wait
Abbreviation: ALS, amyotrophic lateral sclerosis. 夽 Delay of diagnosis in amyotrophic lateral sclerosis (parts of the material were presented as a poster at the Eighteenth Meeting of the European Neurological Society, June 7–11, 2008, Nice, France). ∗ Corresponding author at: Department of Neurology, Alfried Krupp von Bohlen und Halbach Hospital, Alfried-Krupp-Strasse 21, 45117 Essen, Germany. Tel.: +49 201 424 41 424. E-mail address: [email protected] (M. Kraemer). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.10.014
until they are unquestionably ill [3,6–16]. Practical clinical reasons are cited for failure to make a timely and accurate diagnosis [3]. Initial symptoms of ALS mimic spinal cord diseases, mononeuropathies and several neurological syndromes that may postpone a correct diagnosis [17]. With the advent of a specific biological therapy for ALS there is an increasing imperative for early diagnosis. As new, more effective therapies become available, this will become more important. It is intuitively probable that early therapy will prevent disability in this otherwise relentlessly progressive disorder [18]. The aim of our study was to investigate if diagnostic and therapeutic parameters have influence on the time of diagnosis. In literature, there are only little data about this topic [4,6,13–15]. 2. Materials and methods We retrospectively reviewed the medical records of 100 consecutive ALS patients focusing on clinical and diagnostic data, the timing of diagnosis and treatments attributed to the onset of symptoms of ALS. If patients underwent therapy prior to diagnosis of ALS, we explored whether there was an improvement of symptoms due to this treatment. We compared different groups of patients: men and women, patients with bulbar symptoms and symptoms of the upper motoneuron at the beginning of the disease, those who had surgery or another therapy prior to diagnosis with patients who did not present these criteria and patients at different ages. Statistical analysis was done with the Mann–Whitney test.
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M. Kraemer et al. / Clinical Neurology and Neurosurgery 112 (2010) 103–105
Table 1 Subject characteristists and statistical data (bold values are statistically significant). n
Gender (n)
Age (years)
Time to diagnosis (months)
p-Value
F
M
Mean
Median
Mean
Median
100 63 37
37 0 37
63 63 0
64.4 ± 9.7 64.1 ± 9.6 64.9 ± 10.0
65.0 65.0 65.0
13.7 ± 14.8 14.3 ± 17.4 12.6 ± 8.7
10.5 10.0 11.0
p = 0.793
Operation No operation
12 88
5 32
7 56
68.1 ± 5.0 63.8 ± 10.1
66.0 65.0
18.4 ± 8.6 13.2 ± 15.2
16.0 10.0
p = 0.011
Bulbar onset No bulbar onset
35 65
16 21
19 44
63.9 ± 10.9 64.6 ± 9.0
66.0 65.0
9.0 ± 6.5 16.4 ± 17.5
7.0 12.0
p = 0.004
Age <45 years Age >45 years Age <55 years Age >55 years
4 96 15 85
0 37 7 30
4 59 8 55
40.0 65.4 47.1 67.8
± ± ± ±
41.0 65.0 49.0 66.0
5.5 13.9 9.5 14.3
± ± ± ±
2.1 15.0 8.3 15.6
5.5 11.0 8.0 12.0
UMS Non-USM
47 53
18 19
29 34
65.7 ± 8.5 63.1 ± 10.6
66.0 64.5
14.8 ± 18.3 12.8 ± 11.3
12.0 10.0
p = 0.423
Other diagnoses No other diagnoses
44 56
16 21
28 35
67.0 ± 7.2 62.2 ± 10.9
66.0 63.0
15.7 ± 18.8 12.1 ± 10.6
12.0 9.0
p = 0.153
Fasciculation No fasciculation
70 30
19 18
51 11
63.3 ± 9.7 66.9 ± 9.3
65 66
13.4 ± 15.5 14.2 ± 13.2
10.5 10.5
p = 0.980
Spinal MRI No spinal MRI
19 81
6 31
13 50
63.6 ± 7.7 64.5 ± 10.1
66.0 65.0
22.1 ± 28.8 11.9 ± 9.1
12.5 10.0
p = 0.211
Overall Male Female
3. Results We reviewed the medical records of 37 female and 63 male patients. Overall, the mean age of the patients was 64.4 years (Table 1), their mean time from first symptoms to diagnosis was 13.7 months. Mean time to diagnosis was 12.6 months for women and 14.3 months for men (p = 0.793). Comparing differences in mean time to diagnosis between patients that were younger than 45 years (n = 4, time to diagnosis 5.5 months) or younger than 55 years (n = 15, 9.5 months) and the group of respectively older patients revealed a trend to shorter mean time to diagnosis in younger patients without statistical significance (p = 0.052 when younger than 45 years; p = 0.079 when younger than 54 years). Twelve patients in our study group (12%) underwent surgery due to symptoms retrospectively attributable to ALS, ten of these patients underwent spinal decompression surgery, while just three showed sensible symptoms. One patient had a strumectomia because of retrospectively diagnosed bulbar symptoms and another one had sulcus ulnaris decompression surgery due to paraesthesia and weakness of the hand. An improvement of symptoms was documented just in one case of spinal decompression surgery. Diagnosis of ALS was significantly earlier for non-operated patients (13.2 months) compared to the group of operated patients (18.4 months, p = 0.01). Thirty-five of our study patients (35%) had bulbar onset symptoms. Their mean time from first symptoms to diagnosis was 9 months, which is a significant difference compared to the group of patients without bulbar onset (16.4 months, p = 0.004). In over half of the patients (n = 53) there was no documented disease of the upper motoneuron. Time to diagnosis in this group was 12.8 months. The difference in time to diagnosis is not significant compared to the group of patients with upper motoneuron disease (14.8 months, p = 0.423). In 44 patients (44%) other clinical diagnoses were considered and medically treated prior to correct diagnosis. Considered differential diagnoses were spinal cord/nerve root impingement in 9 cases, mononeuropathies in 6 cases, cerebral ischemia in 3 cases and 23 other differential diagnoses in the other subjects. Compared to the group of patients without other diagnoses, there was no
4.9 8.4 5.5 6.5
p = 0.052 p = 0.079
significant difference regarding their mean time from first symptoms to diagnosis (with other diagnosis 15.7 months; without other diagnosis 12.1 months, p = 0.153). 4. Discussion To the best of our knowledge only two studies dealt with the problem of inappropriate surgeries resulting from misdiagnosis of early ALS. In the study of the American neurological scientific team of Jayashri Srinivasan and colleagues 13% of their cohort of 260 ALS patients have undergone surgery for symptoms which were later attributed to early ALS [12]. Symptoms leading to surgery were weakness, dysphagia, breathing difficulties, speech disturbances and muscle atrophy. Pain was almost never the presenting symptom. Yamada et al. reported coexistence of cervical spondylosis with ALS. In their review of 63 patients half were diagnosed with this [18]. The American neurosurgical and neurological working group of Yoshor and colleagues reported decompressive spinal surgery because of ALS attributable symptoms in 4.2% of their large database of ALS patients [16]. There is also little existing literature about predictors of delay of diagnosis. The Italian group of Zoccolella et al. investigated predictors of delay in diagnosis and likelihood for trial entry [4]. In their population-based series, diagnostic delay was longer in subjects with spinal onset, an age between 65 and 75 years and fasciculation as first symptoms. A significant number of subjects with ALS, characterised by a limited spread of signs, were not trial eligible while alive. Consistent with our data Househam et al. identified bulbar symptoms as more likely to lead to a correct diagnosis than limb-onset features [8]. In this cohort, studied in England and Wales, the mean time from onset to diagnosis was 16.2 months [8]. Our study reveals that 12% of our cohort underwent inappropriate surgery prior to the diagnosis of ALS. This is similar to the study of Srinivasan and colleagues with 13% of patients who underwent inappropriate surgery [12]. In a smaller cohort of 33 patients 17% underwent laminectomies because of misdiagnosis [6]. In our study bulbar symptoms at onset lead to significant abbreviation of mean time from first symptoms to diagnosis. On the other hand, patients with surgery showed a delay of correct diagnosis of approximately 6 months. Previously medically treated patients because of other
M. Kraemer et al. / Clinical Neurology and Neurosurgery 112 (2010) 103–105
clinical diagnoses (43%) presented no significant delay of mean time to diagnosis. The same was true for patients without upper motoneuron signs (51%) although regarding the El Escorial criteria of diagnosis of ALS disease of the upper motoneuron is a necessary symptom to make a diagnosis. Belsh and Schiffmann found the same percentage of initially misdiagnosed patients (43%) in their cohort of 33 patients with a similar percentage of operated patients (17%) [6]. In contrast to our data the mean time to correct diagnosis was significantly greater for the misdiagnosed group than in the rest of the patients in Belsh’s study [6]. Younger individuals being less likely to develop ALS would be expected to undergo more extensive testing to find something else but did not show a delay of diagnosis in our study. It could be suspected that these individuals were more likely to seek medical attention earlier than older individuals because of motivational factors. Several limitations in the interpretation of our data must be noted. The number of patients was small and there could be a referral bias. Our study implies the surgeries in 12 patients were inappropriate because their symptoms were retrospectively attributable to ALS. However, it also can be discussed that lack of improvement does not mean the surgery was unnecessary since patients can have ALS with spinal cord/nerve root impingement with may warrant surgery and be improved by it. Maybe it is the progression of the underlying ALS which can mask any apparent benefit. But other studies analysed smaller cohorts dealing with the same definition of inappropriate surgeries [6,13] and our results are consistent with other studies [6,12]. The clinically relevant question is if it is of benefit for the individual patient to diagnose this disease early. The development of drugs altering the course of ALS raises hopes that early treatment will be more effective than treatment administered later on in the disease process [1]. The American scientist B.R. Brooks discussed some diagnostic dilemmas in ALS [1]: What role will early diagnosis have to play? Can we diagnose and administer treatment that might stop disease progression? What would be the emotional damage to a patient who has mild signs of ALS but is given an early diagnosis? Most patients receiving a diagnosis of ALS will experience fear, anxiety and depression [3]. However, the benefits of an early diagnosis of ALS include the right of the patient to know the truth as soon as possible, the psychological advantage to the patient and family, and the opportunity to gain admission to ongoing clinical trials before the disease is advanced, which would make pharmacological therapy less effective [3]. In addition, an earlier diagnosis will allow the patient and family to plan the future more effectively [3,19]. Furthermore, we must be aware of the possibility of misdiagnoses and must exercise clinical acumen in avoiding costly and unnecessary surgery in ALS patients [16]. A specific and sensitive biological marker would be necessary to enable an earlier diagnosis. The final goal will be the development of cheap biochemical markers for the screening of populations at risk. There is an intensive search for diagnostic markers in ALS but actually they are not appropriate for the use in individual patients [20–24].
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Our study confirms that diagnosis of ALS is still a common clinical problem and reveals the need for improvement of diagnostic criteria. Much should be done to help patients with ALS lead more comfortable and functional lives [3]. Acknowledgement We want to express heartfelt thanks to Ms. M. Herold, MD for important help and procreative discussions. References [1] Brooks BR. Diagnostic dilemmas in amyotrophic lateral sclerosis. J Neurol Sci 1999;165(Suppl.):1–18. [2] Beghi E, Balzarini C, Bogliun G, Logroscino G, Manfredi L, Mazzini L, et al. Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis. Neuroepidemiology 2002;21:265–70. [3] Cristini J. Misdiagnosis and missed diagnoses in patients with ALS. JAAPA 2006;112:10. [4] Zoccolella S, Beghi E, Palagano G, Fraddosio A, Samarelli V, Lamberti P, et al. Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients. A population-based study. J Neurol Sci 2006;250:45–9. [5] Nodera H, Izumi Y, Kaji R. New diagnostic criteria of ALS (Awaji criteria). Brain Nerve 2001;59:1023–9. [6] Belsh JM, Schiffmann PL. Misdiagnosis in patients with amyotrophic lateral sclerosis. Arch Intern Med 1990;150:2301–5. [7] de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 2008;119:497–503. [8] Househam E, Swah M. Diagnostic delay in amyotrophic lateral sclerosis: what scope for improvement? J Neurol Sci 2000;180:76–81. [9] Baek WS, Desai NP. ALS: pitfalls in the diagnosis. Pract Neurol 2007;7(74–81):33–6. [10] Strong MJ. Simplifying the approach: what can we do? Neurology 1999:31–6. [11] Swash M. Early diagnosis of ALS/MND. J Neurol Sci 1998;160:33–6. [12] Srinivasan J, Scala S, Jones HR, Salah F, Russell JA. Inappropriate surgeries resulting from misdiagnosis of early amyotrophic lateral sclerosis. Muscle Nerve 2006;34:359–60. [13] Torny F, Lacoste M, Nguyen JM, Tymoczko-Nguyen ME, Couratier P. Analysis of reasons for the late diagnosis of amyotrophic lateral sclerosis. Rev Neurol 2006;162:617–22. [14] Davenport RJ, Swingler RJ, Chancellor AM, Warlow CP. Avoiding false positive diagnoses of motor neuron desease: lessons from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry 1996;60:147–51. [15] Belsh JM. ALS diagnostic criteria of El Escorial revisited: do they meet the needs of the clinicians as well as researchers? Amyotroph Lateral Scler Other Motor Neuron Disord 2000;(Suppl. 1):57–60. [16] Yoshor D, Klugh A, Appel SH, Haverkamp LJ. Incidence and characteristics of spinal decompression surgery after the onset of symptoms of amyotrophic lateral sclerosis. Neurosurgery 2005;57:984–9. [17] Pinto S, de Carvalho M. Amyotrophic lateral sclerosis patients and ocular ptosis. Clin Neurol Neurosurg 2008;110:168–70. [18] Yamada M, Furukawa Y, Hirohata M. Amyotrophic lateral sclerosis: frequent complications by cervical spondylosis. J Orthop Sci 2003;8:878–816. [19] Soremba, Edith M. Geschenkte Lebensjahre: Wir waren trotz ALS-Diagnose sehr glücklich. Auflage: Geest-Verlag; 1 (2005). ISBN-13:978-3937844497. [20] Belsh JM. Diagnostic challenges in ALS. Neurology 1999;53:26–30. [21] Blijham PJ, Schelhaas HJ, Ter Laak HJ. Early diagnosis of ALS: the search for signs of denervation in clinically normal muscles. J Neurol Sci 2007;263:154–7. [22] Dengler R, von Neuhoff N, Bufler J, Krampfl K, Peschel T, Grosskreutz J. Amyotrophic lateral sclerosis: new developments in diagnostic markers. Neurodegener Dis 2005;2:177–84. [23] Karitzky J, Ludolph AC. Imaging and neurochemical markers for diagnosis and disease progression in ALS. J Neurol Sci 2001;191:35–41. [24] Yamazaki T, Suzuki M, Irie T, Watanabe T, Mikami H, Ono S. Amyotrophic lateral sclerosis associated with anti-GalNAc-GD1a antibodies. Clin Neurol Neurosurg 2008;110:722–4.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis夽 Markus Kraemer ∗ , Melanie Buerger, Peter Berlit Department of Neurology, Alfried Krupp von Bohlen und Halbach Hospital, Alfried-Krupp-Strasse 21, 45117 Essen, Germany
a r t i c l e
i n f o
Article history: Received 30 January 2009 Received in revised form 15 August 2009 Accepted 3 October 2009
Keywords: Amyotrophic lateral sclerosis Delay of diagnosis Diagnostic problems Inappropriate surgery Time to diagnosis
a b s t r a c t Objective: Initial symptoms of amyotrophic lateral sclerosis (ALS) mimic several neurological syndromes that may decelerate a correct diagnosis. The aim of our study was to investigate if diagnostic and therapeutic parameters have influence on the time of diagnosis. Methods: We retrospectively reviewed the medical records of 100 consecutive ALS patients focusing on clinical and diagnostic data, the timing of diagnosis and treatments attributed to the onset of symptoms of ALS. Results: Among 100 consecutive patients with ALS, 12% underwent surgery due to symptoms retrospectively attributable to ALS. The comparison of duration from first symptoms to correct diagnosis showed a significant difference between operated and non-operated patients. 35% of all ALS patients had bulbar onset symptoms. The mean time from first symptoms to diagnosis was 9 months in this group. In patients without bulbar onset it was 16.4 months which also represents a significant difference. In 44% of patients other diagnoses were considered and medically treated previous to correct diagnosis, but there was no significant delay of diagnosis. Conclusion: Our study confirms that diagnosis of ALS is still a common clinical problem and shows the need of sensitive and specific diagnostic tests. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Amyotrophic lateral sclerosis (ALS), a progressive and fatal disease with degeneration of motor neurons in the brain and the spinal cord, was described in 1881 by the French neurologist Jean-Martin Charcot. It is generally felt that the clinical picture of ALS is easy to recognise in its fully developed form [1]. In 1990, international experts for ALS met in a Spanish palace-monastery, El Escorial. The resulting consensus document on ALS diagnostic criteria was published in its final version in 1994 [2,3]. The El Escorial, the revised Airlie House and the Awaji diagnostic criteria for ALS were introduced to select patients for clinical trials [4–10]. However several variations early in the course of ALS make the diagnosis more challenging and allow for the possibility of an alternative, incorrect diagnosis [1]. There might be various reasons diagnosis may be delayed, including the perception of people that it is a desirable character trait to delay seeking help for vague symptoms and wait
Abbreviation: ALS, amyotrophic lateral sclerosis. 夽 Delay of diagnosis in amyotrophic lateral sclerosis (parts of the material were presented as a poster at the Eighteenth Meeting of the European Neurological Society, June 7–11, 2008, Nice, France). ∗ Corresponding author at: Department of Neurology, Alfried Krupp von Bohlen und Halbach Hospital, Alfried-Krupp-Strasse 21, 45117 Essen, Germany. Tel.: +49 201 424 41 424. E-mail address: [email protected] (M. Kraemer). 0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2009.10.014
until they are unquestionably ill [3,6–16]. Practical clinical reasons are cited for failure to make a timely and accurate diagnosis [3]. Initial symptoms of ALS mimic spinal cord diseases, mononeuropathies and several neurological syndromes that may postpone a correct diagnosis [17]. With the advent of a specific biological therapy for ALS there is an increasing imperative for early diagnosis. As new, more effective therapies become available, this will become more important. It is intuitively probable that early therapy will prevent disability in this otherwise relentlessly progressive disorder [18]. The aim of our study was to investigate if diagnostic and therapeutic parameters have influence on the time of diagnosis. In literature, there are only little data about this topic [4,6,13–15]. 2. Materials and methods We retrospectively reviewed the medical records of 100 consecutive ALS patients focusing on clinical and diagnostic data, the timing of diagnosis and treatments attributed to the onset of symptoms of ALS. If patients underwent therapy prior to diagnosis of ALS, we explored whether there was an improvement of symptoms due to this treatment. We compared different groups of patients: men and women, patients with bulbar symptoms and symptoms of the upper motoneuron at the beginning of the disease, those who had surgery or another therapy prior to diagnosis with patients who did not present these criteria and patients at different ages. Statistical analysis was done with the Mann–Whitney test.
104
M. Kraemer et al. / Clinical Neurology and Neurosurgery 112 (2010) 103–105
Table 1 Subject characteristists and statistical data (bold values are statistically significant). n
Gender (n)
Age (years)
Time to diagnosis (months)
p-Value
F
M
Mean
Median
Mean
Median
100 63 37
37 0 37
63 63 0
64.4 ± 9.7 64.1 ± 9.6 64.9 ± 10.0
65.0 65.0 65.0
13.7 ± 14.8 14.3 ± 17.4 12.6 ± 8.7
10.5 10.0 11.0
p = 0.793
Operation No operation
12 88
5 32
7 56
68.1 ± 5.0 63.8 ± 10.1
66.0 65.0
18.4 ± 8.6 13.2 ± 15.2
16.0 10.0
p = 0.011
Bulbar onset No bulbar onset
35 65
16 21
19 44
63.9 ± 10.9 64.6 ± 9.0
66.0 65.0
9.0 ± 6.5 16.4 ± 17.5
7.0 12.0
p = 0.004
Age <45 years Age >45 years Age <55 years Age >55 years
4 96 15 85
0 37 7 30
4 59 8 55
40.0 65.4 47.1 67.8
± ± ± ±
41.0 65.0 49.0 66.0
5.5 13.9 9.5 14.3
± ± ± ±
2.1 15.0 8.3 15.6
5.5 11.0 8.0 12.0
UMS Non-USM
47 53
18 19
29 34
65.7 ± 8.5 63.1 ± 10.6
66.0 64.5
14.8 ± 18.3 12.8 ± 11.3
12.0 10.0
p = 0.423
Other diagnoses No other diagnoses
44 56
16 21
28 35
67.0 ± 7.2 62.2 ± 10.9
66.0 63.0
15.7 ± 18.8 12.1 ± 10.6
12.0 9.0
p = 0.153
Fasciculation No fasciculation
70 30
19 18
51 11
63.3 ± 9.7 66.9 ± 9.3
65 66
13.4 ± 15.5 14.2 ± 13.2
10.5 10.5
p = 0.980
Spinal MRI No spinal MRI
19 81
6 31
13 50
63.6 ± 7.7 64.5 ± 10.1
66.0 65.0
22.1 ± 28.8 11.9 ± 9.1
12.5 10.0
p = 0.211
Overall Male Female
3. Results We reviewed the medical records of 37 female and 63 male patients. Overall, the mean age of the patients was 64.4 years (Table 1), their mean time from first symptoms to diagnosis was 13.7 months. Mean time to diagnosis was 12.6 months for women and 14.3 months for men (p = 0.793). Comparing differences in mean time to diagnosis between patients that were younger than 45 years (n = 4, time to diagnosis 5.5 months) or younger than 55 years (n = 15, 9.5 months) and the group of respectively older patients revealed a trend to shorter mean time to diagnosis in younger patients without statistical significance (p = 0.052 when younger than 45 years; p = 0.079 when younger than 54 years). Twelve patients in our study group (12%) underwent surgery due to symptoms retrospectively attributable to ALS, ten of these patients underwent spinal decompression surgery, while just three showed sensible symptoms. One patient had a strumectomia because of retrospectively diagnosed bulbar symptoms and another one had sulcus ulnaris decompression surgery due to paraesthesia and weakness of the hand. An improvement of symptoms was documented just in one case of spinal decompression surgery. Diagnosis of ALS was significantly earlier for non-operated patients (13.2 months) compared to the group of operated patients (18.4 months, p = 0.01). Thirty-five of our study patients (35%) had bulbar onset symptoms. Their mean time from first symptoms to diagnosis was 9 months, which is a significant difference compared to the group of patients without bulbar onset (16.4 months, p = 0.004). In over half of the patients (n = 53) there was no documented disease of the upper motoneuron. Time to diagnosis in this group was 12.8 months. The difference in time to diagnosis is not significant compared to the group of patients with upper motoneuron disease (14.8 months, p = 0.423). In 44 patients (44%) other clinical diagnoses were considered and medically treated prior to correct diagnosis. Considered differential diagnoses were spinal cord/nerve root impingement in 9 cases, mononeuropathies in 6 cases, cerebral ischemia in 3 cases and 23 other differential diagnoses in the other subjects. Compared to the group of patients without other diagnoses, there was no
4.9 8.4 5.5 6.5
p = 0.052 p = 0.079
significant difference regarding their mean time from first symptoms to diagnosis (with other diagnosis 15.7 months; without other diagnosis 12.1 months, p = 0.153). 4. Discussion To the best of our knowledge only two studies dealt with the problem of inappropriate surgeries resulting from misdiagnosis of early ALS. In the study of the American neurological scientific team of Jayashri Srinivasan and colleagues 13% of their cohort of 260 ALS patients have undergone surgery for symptoms which were later attributed to early ALS [12]. Symptoms leading to surgery were weakness, dysphagia, breathing difficulties, speech disturbances and muscle atrophy. Pain was almost never the presenting symptom. Yamada et al. reported coexistence of cervical spondylosis with ALS. In their review of 63 patients half were diagnosed with this [18]. The American neurosurgical and neurological working group of Yoshor and colleagues reported decompressive spinal surgery because of ALS attributable symptoms in 4.2% of their large database of ALS patients [16]. There is also little existing literature about predictors of delay of diagnosis. The Italian group of Zoccolella et al. investigated predictors of delay in diagnosis and likelihood for trial entry [4]. In their population-based series, diagnostic delay was longer in subjects with spinal onset, an age between 65 and 75 years and fasciculation as first symptoms. A significant number of subjects with ALS, characterised by a limited spread of signs, were not trial eligible while alive. Consistent with our data Househam et al. identified bulbar symptoms as more likely to lead to a correct diagnosis than limb-onset features [8]. In this cohort, studied in England and Wales, the mean time from onset to diagnosis was 16.2 months [8]. Our study reveals that 12% of our cohort underwent inappropriate surgery prior to the diagnosis of ALS. This is similar to the study of Srinivasan and colleagues with 13% of patients who underwent inappropriate surgery [12]. In a smaller cohort of 33 patients 17% underwent laminectomies because of misdiagnosis [6]. In our study bulbar symptoms at onset lead to significant abbreviation of mean time from first symptoms to diagnosis. On the other hand, patients with surgery showed a delay of correct diagnosis of approximately 6 months. Previously medically treated patients because of other
M. Kraemer et al. / Clinical Neurology and Neurosurgery 112 (2010) 103–105
clinical diagnoses (43%) presented no significant delay of mean time to diagnosis. The same was true for patients without upper motoneuron signs (51%) although regarding the El Escorial criteria of diagnosis of ALS disease of the upper motoneuron is a necessary symptom to make a diagnosis. Belsh and Schiffmann found the same percentage of initially misdiagnosed patients (43%) in their cohort of 33 patients with a similar percentage of operated patients (17%) [6]. In contrast to our data the mean time to correct diagnosis was significantly greater for the misdiagnosed group than in the rest of the patients in Belsh’s study [6]. Younger individuals being less likely to develop ALS would be expected to undergo more extensive testing to find something else but did not show a delay of diagnosis in our study. It could be suspected that these individuals were more likely to seek medical attention earlier than older individuals because of motivational factors. Several limitations in the interpretation of our data must be noted. The number of patients was small and there could be a referral bias. Our study implies the surgeries in 12 patients were inappropriate because their symptoms were retrospectively attributable to ALS. However, it also can be discussed that lack of improvement does not mean the surgery was unnecessary since patients can have ALS with spinal cord/nerve root impingement with may warrant surgery and be improved by it. Maybe it is the progression of the underlying ALS which can mask any apparent benefit. But other studies analysed smaller cohorts dealing with the same definition of inappropriate surgeries [6,13] and our results are consistent with other studies [6,12]. The clinically relevant question is if it is of benefit for the individual patient to diagnose this disease early. The development of drugs altering the course of ALS raises hopes that early treatment will be more effective than treatment administered later on in the disease process [1]. The American scientist B.R. Brooks discussed some diagnostic dilemmas in ALS [1]: What role will early diagnosis have to play? Can we diagnose and administer treatment that might stop disease progression? What would be the emotional damage to a patient who has mild signs of ALS but is given an early diagnosis? Most patients receiving a diagnosis of ALS will experience fear, anxiety and depression [3]. However, the benefits of an early diagnosis of ALS include the right of the patient to know the truth as soon as possible, the psychological advantage to the patient and family, and the opportunity to gain admission to ongoing clinical trials before the disease is advanced, which would make pharmacological therapy less effective [3]. In addition, an earlier diagnosis will allow the patient and family to plan the future more effectively [3,19]. Furthermore, we must be aware of the possibility of misdiagnoses and must exercise clinical acumen in avoiding costly and unnecessary surgery in ALS patients [16]. A specific and sensitive biological marker would be necessary to enable an earlier diagnosis. The final goal will be the development of cheap biochemical markers for the screening of populations at risk. There is an intensive search for diagnostic markers in ALS but actually they are not appropriate for the use in individual patients [20–24].
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Our study confirms that diagnosis of ALS is still a common clinical problem and reveals the need for improvement of diagnostic criteria. Much should be done to help patients with ALS lead more comfortable and functional lives [3]. Acknowledgement We want to express heartfelt thanks to Ms. M. Herold, MD for important help and procreative discussions. References [1] Brooks BR. Diagnostic dilemmas in amyotrophic lateral sclerosis. J Neurol Sci 1999;165(Suppl.):1–18. [2] Beghi E, Balzarini C, Bogliun G, Logroscino G, Manfredi L, Mazzini L, et al. Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis. Neuroepidemiology 2002;21:265–70. [3] Cristini J. Misdiagnosis and missed diagnoses in patients with ALS. JAAPA 2006;112:10. [4] Zoccolella S, Beghi E, Palagano G, Fraddosio A, Samarelli V, Lamberti P, et al. Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients. A population-based study. J Neurol Sci 2006;250:45–9. [5] Nodera H, Izumi Y, Kaji R. New diagnostic criteria of ALS (Awaji criteria). Brain Nerve 2001;59:1023–9. [6] Belsh JM, Schiffmann PL. Misdiagnosis in patients with amyotrophic lateral sclerosis. Arch Intern Med 1990;150:2301–5. [7] de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 2008;119:497–503. [8] Househam E, Swah M. Diagnostic delay in amyotrophic lateral sclerosis: what scope for improvement? J Neurol Sci 2000;180:76–81. [9] Baek WS, Desai NP. ALS: pitfalls in the diagnosis. Pract Neurol 2007;7(74–81):33–6. [10] Strong MJ. Simplifying the approach: what can we do? Neurology 1999:31–6. [11] Swash M. Early diagnosis of ALS/MND. J Neurol Sci 1998;160:33–6. [12] Srinivasan J, Scala S, Jones HR, Salah F, Russell JA. Inappropriate surgeries resulting from misdiagnosis of early amyotrophic lateral sclerosis. Muscle Nerve 2006;34:359–60. [13] Torny F, Lacoste M, Nguyen JM, Tymoczko-Nguyen ME, Couratier P. Analysis of reasons for the late diagnosis of amyotrophic lateral sclerosis. Rev Neurol 2006;162:617–22. [14] Davenport RJ, Swingler RJ, Chancellor AM, Warlow CP. Avoiding false positive diagnoses of motor neuron desease: lessons from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry 1996;60:147–51. [15] Belsh JM. ALS diagnostic criteria of El Escorial revisited: do they meet the needs of the clinicians as well as researchers? Amyotroph Lateral Scler Other Motor Neuron Disord 2000;(Suppl. 1):57–60. [16] Yoshor D, Klugh A, Appel SH, Haverkamp LJ. Incidence and characteristics of spinal decompression surgery after the onset of symptoms of amyotrophic lateral sclerosis. Neurosurgery 2005;57:984–9. [17] Pinto S, de Carvalho M. Amyotrophic lateral sclerosis patients and ocular ptosis. Clin Neurol Neurosurg 2008;110:168–70. [18] Yamada M, Furukawa Y, Hirohata M. Amyotrophic lateral sclerosis: frequent complications by cervical spondylosis. J Orthop Sci 2003;8:878–816. [19] Soremba, Edith M. Geschenkte Lebensjahre: Wir waren trotz ALS-Diagnose sehr glücklich. Auflage: Geest-Verlag; 1 (2005). ISBN-13:978-3937844497. [20] Belsh JM. Diagnostic challenges in ALS. Neurology 1999;53:26–30. [21] Blijham PJ, Schelhaas HJ, Ter Laak HJ. Early diagnosis of ALS: the search for signs of denervation in clinically normal muscles. J Neurol Sci 2007;263:154–7. [22] Dengler R, von Neuhoff N, Bufler J, Krampfl K, Peschel T, Grosskreutz J. Amyotrophic lateral sclerosis: new developments in diagnostic markers. Neurodegener Dis 2005;2:177–84. [23] Karitzky J, Ludolph AC. Imaging and neurochemical markers for diagnosis and disease progression in ALS. J Neurol Sci 2001;191:35–41. [24] Yamazaki T, Suzuki M, Irie T, Watanabe T, Mikami H, Ono S. Amyotrophic lateral sclerosis associated with anti-GalNAc-GD1a antibodies. Clin Neurol Neurosurg 2008;110:722–4.