Brain, Vol. 126, No. 5, 1036-1047,
May 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg117
Sporadic lower motor neuron disease with adult onset: classification of subtypes
Departments of 1 Neurology and 2 Clinical Neurophysiology of the Rudolf Magnus Institute for Neurosciences, 3 Julius Centre for General Practice and Patient Oriented Research, University Medical Centre Utrecht and the 4 Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands
Correspondence to: L. H. Van den Berg, MD, PhD, Department of Neurology, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands E-mail: l.h.vandenberg{at}neuro.azu.nl
Received July 20, 2002. Revised October 13, 2002. Accepted December 2, 2002.
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The discovery of the genetic basis of hereditary lower motor neuron disease (LMND) and the recognition of multifocal motor neuropathy as a distinct clinical entity necessitate a new classification of LMND. To this end, we studied the clinical and electrophysiological features of 49 patients with sporadic adult-onset LMND in a cross-sectional study. Disease duration was more than 4 years to exclude the majority of patients with amyotrophic lateral sclerosis. Based on the pattern of weakness, we identified three groups: 13 patients with generalized weakness (group 1); eight patients with symmetrical, distal muscle weakness (group 2); and 28 patients with non-generalized asymmetrical weakness of the arms in most patients (group 3). Group 3 could be subdivided into patients with weakness in predominantly the distal (group 3a) or the proximal (group 3b) muscle groups, both with disease progression to adjacent spinal cord segments. Distinctive features of group 1 were an older age at onset, more severe weakness and muscle atrophy, lower reflexes, greater functional impairment, more widespread abnormalities on concentric needle EMG, respiratory insufficiency and serum M-protein. In groups 2 and 3, concentric needle EMG findings also suggested a more widespread disease process. Retrospectively, the prognosis of sporadic adult-onset LMND appears to be favourable, because clinical abnormalities were still confined to one limb in most patients after a median disease duration of 12 years. We propose to classify the patients in the different subgroups as slowly progressive spinal muscular atrophy (group 1), distal spinal muscular atrophy (group 2), segmental distal spinal muscular atrophy (group 3a) and segmental proximal spinal muscular atrophy (group 3b). The described clinical phenotypes may help to distinguish between different LMND forms.
Keywords: lower motor neuron disease; motor neuron disease; progressive spinal muscular atrophy; amyotrophic lateral sclerosis; multifocal motor neuropathy
Abbreviations: ADL= activities of daily living; ALS = amyotrophic lateral sclerosis; CMAP = compound muscle action potential; HMSN = hereditary motor and sensory neuropathy; LLN = lower limit of normal; LMN = lower motor neuron; LMND = lower motor neuron disease; MMN = multifocal motor neuropathy; MND = motor neuron disease; MRC = Medical Research Council; MUP = motor unit potential; NINDS = National Institute of Neurological Diseases and Stroke; SMA = spinal muscular atrophy; SMN gene = survival motor neuron gene; UMN = upper motor neuron
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Introduction |
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Amyotrophic lateral sclerosis (ALS) is the most common and most severe form of the motor neuron diseases, eventually leading to death due to respiratory insufficiency within a few years. ALS is characterized by the degeneration of lower motor neurons (LMN) in the anterior horn of the spinal cord or in the brainstem and of upper motor neurons (UMN) in the motor cortex of the brain. In 1994, the El Escorial criteria for ALS were proposed, based on clinical features in four (bulbar, cervical, thoracic and lumbosacral) body regions (Brooks, 1994
). To diagnose definite and probable ALS, both UMN and LMN signs have to present in two or more regions. Possible ALS is diagnosed when UMN and LMN signs are found in one region. The diagnosis is less certain in patients with only LMN signs in two or more regions. These patients, who were diagnosed as having suspected ALS according to the 1994 El Escorial criteria and for whom a diagnostic category no longer exists in the 1998 revised El Escorial criteria (www.wfnals.org), have progressive muscle atrophy and muscle weakness, but as yet no UMN signs. These patients have been described earlier as having progressive (spinal) muscular atrophy (Aran, 1850; Norris, 1991). However, patients with only LMN signs but without overt progression have also been described under various names (Hirayama et al., 1963; Harding and Thomas, 1980; Prabhakar et al., 1981; Kaeser et al., 1983; Gourie-Devi et al., 1984). Therefore, the term lower motor neuron disease (LMND) may be used for all diseases in which only LMN signs are found.
In large series of patients with motor neuron disease (MND), approximately 10% have LMN signs only (Müller 1952; Chancellor et al., 1993; Norris et al., 1993; Haverkamp et al., 1995; Traynor et al., 2000). Whether LMND is a distinct nosological entity, separate from ALS, has been debated since Aran first described LMND in 1850 (Aran, 1850). Clinical studies of patients presenting with LMND indicate that a substantial number of patients do develop ALS (Norris, 1991). In a prospective population-based study of ALS, 70% of patients with LMN signs had developed UMN and bulbar signs characteristic of ALS after six years (Traynor et al., 2000). Therefore, probably fewer than 10% of patients with MND will continue to show LMN signs only. To exclude the majority of patients with ALS, we required a disease duration of more than 4 years.
Clinical, pathological and, more recently, genetic, electrophysiological and immunological findings can help to distinguish patients with LMND who never develop ALS from patients with typical ALS. For example, a deletion of the telomeric survival motor neuron (SMN) gene on chromosome 5q13 is found in patients with adult-onset SMN gene-linked spinal muscular atrophy (SMA) (Cobben et al., 1995; Brahe et al., 1995). These patients have symmetrical muscle wasting and weakness of the proximal muscle groups of the limbs and trunk. Spinobulbar muscular atrophy or Kennedy’s disease is another hereditary form of LMND and is caused by an expansion of CAG trinucleotide repeats in the androgen receptor gene (Kennedy et al., 1968; La Spada et al., 1992). Patients present—usually at adult age—with slowly progressive, proximal weakness of the limbs associated with facial weakness. The gene defect in other hereditary forms of LMND has not yet been identified (Jansen et al., 1986; Van den Berg-Vos et al., 2001). Over the last decade, progress has been made in identifying patients with multifocal motor neuropathy (MMN), an immune-mediated LMN disorder. Patients with MMN present with a slowly progressive asymmetrical distal weakness of the limbs. Evidence of persistent motor conduction block on electrophysiological examination is considered the electrodiagnostic hallmark of MMN. Importantly, patients with MMN respond to immunological treatment.
These new developments in DNA-proven hereditary LMND and the differentiation of MMN from LMND on the basis of nerve conduction studies have made some of the earlier reported studies of LMND obsolete. An up-to-date classification of LMND is therefore needed. We describe the clinical and electrophysiological characteristics of 49 patients with sporadic adult-onset LMND and define clinical subtypes.
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Methods |
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Study design and patients
The design of this study was cross-sectional. Initially, we reviewed the records of patients in whom a prior diagnosis of LMND, progressive SMA, focal SMA or segmental SMA was made from 1985 to 2000 at the neuromuscular outpatient clinics of the University Medical Centre Utrecht and the Academic Medical Centre of Amsterdam, both tertiary referral centres for MND in The Netherlands. Subsequently, patients were seen by R.M.V.d.B.-V. or J.V. between 1998 and 2000 for re-appraisal. This consisted of a standardized neurological, laboratory and electrophysiological examination and genetic testing (see below).
Only those patients who fulfilled the following criteria were included: (i) age at onset >18 years; (ii) disease duration of >4 years from the time of onset of weakness; (ii) evidence of LMN involvement on neurological examination (weakness, atrophy and fasciculations); and (iv) electrophysiological evidence of LMN involvement on needle EMG examination.
Exclusion criteria were: (i) familial history of LMND; (ii) deletion in the SMN1 gene or an expansion of CAG-repeats (>40) in the androgen receptor gene; (iii) history of diseases that may mimic LMND (acute poliomyelitis, spinal radiculopathy, diabetic amyotrophy, thyrotoxicosis or hyperparathyroidism); (iv) clinical signs of UMN involvement [pseudobulbar symptoms, clonus of masseter reflex, hyperreflexia (for definition see below) or extensor plantar response]; (v) objective sensory signs on neurological examination; (vi) tracheostomy or intermittent ventilatory assistance; (vii) structural lesions (tumors, intervertebral disk herniation, vascular lesions, syringomyelia) on MRI or myelography of the spinal cord; and (viii) motor conduction block on extensive standardized nerve conduction studies according to previously defined criteria (Van den Berg-Vos et al., 2000).
The following laboratory tests were performed to rule out other diseases: sedimentation rate, haemoglobin, haematocrit, thyroid stimulating hormone, serum immunelectrophoresis with immunofixation, phosphate, calcium (plus, if elevated, parathyroid hormone) and serum IgM anti-GM1 antibodies [the latter as described elsewhere (Van den Berg et al., 1992)].
Clinical evaluation
Muscle strength, muscle atrophy, myotatic reflexes, vital capacity and functional impairment were assessed by R.M.V.d.B.-V. or J.V. Muscle strength was measured by manual muscle testing according to the grading system of the Medical Research Council (MRC) (Medical Research Council, 1976), modified to a nine-point scale (Mendell et al., 1989). Table 1 shows the muscle groups that were measured. Muscle groups were subdivided into upper, middle and lower cervical or lumbosacral regions giving a total of 12 limb regions per patient. Each limb region consisted of two or three myotomes (Table 1). For each limb region, a mean MRC score was calculated by ascribing the following values to the following MRC grades: MRC 5 = 5.00; MRC 5– = 4.67; MRC 4+ = 4.33; MRC 4 = 4.00; MRC 4– = 3.67; MRC 3 = 3.00; MRC 2 = 2.00; MRC 1 = 1.00; MRC 0 = 0.00) (FSH-DY Group, 1997). We considered a muscle group with a MRC score 
4+ as affected and also calculated the number of affected limb regions. The distribution of weakness was ‘symmetrical’ if the difference in weakness on the left versus the right side was <1 on the MRC score in the majority of the affected muscle groups. The presence of muscle atrophy was determined in muscle groups and limb regions. Biceps (upper cervical region), triceps (middle cervical region), knee (middle lumbosacral region) and ankle (lower lumbosacral region) reflexes were scored on both sides according to the National Institute of Neurological Diseases and Stroke (NINDS) myotatic reflex scale (0 = reflex absent, 1 = reflex small, less than normal, 2 = reflex in lower half of normal range, 3 = reflex in upper half of normal range, 4 = subclonus, 5 = clonus) (Hallett, 1993). A reflex score of 4 or 5 was defined as hyperreflexia and was an exclusion criterion. Respiratory vital capacity was measured (Sanjak et al., 2000) and results expressed as a percentage of the predicted normal vital capacity. A value >80% of predicted was considered normal. Functional impairment was assessed using the ALS functional rating scale, a 10-item scale that rates the performance of activities of daily living (ADL), signs and symptoms on a scale from 4 (normal function) to 0 (unable to attempt the task) (maximum 40) (ALS CNTF Treatment Study Group, 1996).
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Electrophysiological examination
The distribution of electrophysiological abnormalities was determined by bilateral concentric needle EMG and assessment of compound muscle action potentials (CMAPs). Concentric needle EMG was performed in the m. biceps brachii (upper cervical region), m. flexor carpi radialis (middle cervical region), m. interosseus dorsalis I (lower cervical region) on both sides, in the mm. erectores spinae near Th 6 left and Th 10 right (thoracic region), and in the m. rectus femoris (upper lumbosacral region), m. tibialis anterior (middle lumbosacral region) and m. gastrocnemius caput laterale (lower lumbosacral region) on both sides. A muscle was considered abnormal if there was spontaneous muscle fibre activity (fibrillations, positive sharp waves or complex repetitive discharges) in at least one insertion, or a severely reduced pattern on maximal voluntary effort mainly consisting of long-lasting polyphasic or giant (>7 mV) motor unit potentials (MUPs) or no insertional and no MUP activity.
CMAPs on stimulation of the most distal site of a nerve were taken from the motor nerve conduction studies that were performed according to a standardized protocol to exclude multifocal motor neuropathy (Van den Berg-Vos et al., 2000). A CMAP was considered abnormal if the amplitude of the negative peak was below the lower limit of normal (LLN) of our laboratory. We assessed the CMAPs of the m. biceps brachii (LLN 3.0 mV, upper cervical region), m. flexor carpi radialis (LLN 2.9 mV, middle cervical region), m. abductor pollicis brevis (LLN 3.5 mV, lower cervical region) on both sides.
Statistical analysis
Differences in the variables between two groups were tested using the non-parametric Mann–Whitney U test. For a comparison of more than two groups, the Kruskal–Wallis test and Fisher’s Exact test for discrete outcome variables were used. A P value <0.05 was considered statistically significant.
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Patients
After reviewing the records of 108 patients, 37 patients were excluded on the basis of a disease duration of <4 years. After re-examination of 71 patients, the diagnosis was changed to MMN in seven patients, to chronic inflammatory demyelinating polyneuropathy in two patients and to myasthenia gravis, inflammatory myopathy, chronic idiopathic axonal polyneuropathy, idiopathic brachial plexus neuropathy, syringomyelia, myopathy, herniated lumbar disk in seven other patients, respectively (Visser et al., 2002
). In one patient, the disease duration was unknown. Three patients had UMN signs and were diagnosed as having ALS. Two patients were excluded because they had refused to undergo electrophysiological examination. The characteristics of the 49 patients who were included in this cross-sectional study are shown in Table 2. A male predominance was found. Onset of weakness was most frequently in one distal upper limb. Two female patients first developed bulbar signs, followed by weakness of the arms. At a median disease duration of 12 years, the number of clinically affected limb regions ranged from 1 to 12. In most limb regions, weakness was associated with muscle wasting and absent or decreased reflexes, although brisk reflexes (score 3 on the NINDS reflex scale) were also observed at the first affected side in a minority of patients. Vital capacity was lower than 80% of predicted in five patients, whose disease durations ranged from 6 to 27 years. Two of these five patients had signs and symptoms of respiratory insufficiency. MRI showed atrophy of the cervical spinal cord in four patients and of the thoracic spinal cord in one patient; in two patients, an additional increased signal intensity was seen (Fig. 1). Two patients had highly elevated titres of IgM anti-GM1 ganglioside antibodies—one with generalized weakness and one with symmetrical distal weakness (see below). The latter patient was one of the four patients who demonstrated atrophy and an increased signal intensity of the cervical spinal cord. Three others had a M-protein: two patients had an IgG lambda monoclonal gammopathy (in one, the diagnosis of multiple myeloma was made after bone marrow examination) and one patient had both an IgG and IgM lambda monoclonal gammopathy.
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Evaluation of subgroups
Patients were subdivided according to the pattern of weakness. Thirteen patients had generalized symmetrical weakness (by definition >6 affected limb regions) (group 1). Of the 36 patients with non-generalized weakness (
6 affected regions), eight patients showed symmetrical weakness (group 2) and 28 patients asymmetrical weakness (group 3) (Table 2). In group 3, 14 patients had more pronounced weakness in the distal (lower cervical or lumbosacral) limb region (group 3a) and 14 patients had more pronounced weakness in the proximal (upper cervical or lumbosacral) limb region (group 3b). Disease duration did not differ between the groups (Table 3). Age at onset was significantly higher in group 1 than in the other groups (Mann–Whitney U test, P < 0.01). The onset of weakness was predominantly distal in the legs in groups 1 and 2, and in the arms in groups 3a and 3b. At neurological examination, weakness was symmetrical in groups 1 and 2, and asymmetrical in group 3a and 3b. The patients of group 1 had more severe weakness, as the mean MRC score per affected region was significantly lower. The patients of group 1 also had muscle atrophy in more limb regions and lower ALS functional rating scale scores. A bulbar onset of symptoms and signs, a vital capacity of <80% and a M-protein were observed in two, five and three patients of group 1, respectively, but not in any patients of the other groups.
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Segmental distribution of weakness
To determine whether specific spinal cord segments were preferentially affected, the percentage of patients with affected muscle groups for each limb region was calculated (Table 4) and the reflexes were assessed. In patients of group 1, weakness and decreased reflexes were found more frequently and were more severe in the legs than in the arms. In addition, weakness was more severe in the lower cervical and lower lumbosacral regions than in the upper and middle cervical and lumbosacral regions. In patients of group 2, weakness and decreased reflexes were found predominantly in the lower cervical and lumbosacral regions. In three of these patients, both arms and legs were affected, with more pronounced weakness in the legs. The legs only were affected in four patients and only the arms in one patient. Of the patients in group 3a, the lower cervical region was most severely affected in 13 patients and the lower lumbosacral region in one patient. In the latter patient, no progression to other limb regions was seen after a disease duration of 22 years. Of the patients with onset in the arms, weakness had progressed over time such that the middle and upper cervical regions were affected at inclusion in the first affected (ipsilateral) arm in 71 and 21% of patients, respectively (Table 4). The upper, middle and lower cervical regions were affected in the last affected (contralateral) arm in 14, 14 and 29% of patients, respectively (data not shown), and the upper lumbosacral region was affected in one patient. This indicates that, in the patients in group 3a, muscle weakness appeared to spread to adjacent spinal cord segments in a segmental pattern. The reflexes were in the normal range, besides the upper cervical region on the first affected side, in which reflexes were brisk (score 3 on the NINDS reflex scale) in half of the patients. Of the patients in group 3b, the upper cervical region was most severely affected in 13 patients and the upper lumbosacral region in one patient. In the latter patient, mild weakness in the upper cervical region on the first affected side was found after a disease duration of 19 years. Of the patients with onset in the arms, the disease had progressed to adjacent spinal cord segments, resulting in weakness at inclusion in the middle and lower cervical regions in the ipsilateral arm in 64 and 36% of patients, respectively (Table 4) and in the upper, middle and lower cervical region in the contralateral arm in 50, 21 and 29% of the patients, respectively (data not shown). The reflexes were in the normal range, besides the biceps reflex (upper cervical region) on the first affected side, which was absent in six and decreased in four of the 14 patients of group 3b. In all groups, the median value of the mean MRC score in the distinct limb regions supported these clinical observations (Fig. 2). Disease variables did not significantly differ between patients in groups 3a and 3b, except for the male to female ratio, which was 9:5 in group 3a and 13:1 in group 3b (P = 0.02).
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Electrophysiological examination
Standardized electrophysiological examination was performed to search for subclinical involvement of the limb regions. Table 4 shows the percentage of patients with weakness, abnormalities on concentric needle EMG and decreased or absent CMAPs for each limb region. In the majority of limb regions of all groups, more patients had abnormalities at concentric needle EMG in a limb region than had weakness of that region. This was especially true for the upper and middle lumbosacral regions of patients in group 2, and for all lumbosacral regions of patients in group 3. In the cervical regions, the percentage of patients with abnormalities on concentric needle EMG was compared with the percentage of patients with decreased or absent CMAPs. In all groups, more patients had abnormalities on concentric needle EMG than had decreased or absent CMAPs. This can be explained by the fact that MUPs and CMAPs remain relatively large due to reinnervation, while both denervation and reinnervation can be detected by concentric needle EMG.
Case reports
Group 1 (generalized weakness)
In 1990, a 56-year-old man developed distal weakness in his left leg followed, in 1993, by distal weakness in the right leg. From 1995 onward, the proximal muscles of both legs became weaker, and walking and climbing stairs became impaired. In 2000, the patient noticed diminished strength and dexterity in both hands. One year later, neurological examination showed distal atrophy in the arms and diffuse atrophy in the legs. Weakness of shoulder abductors, elbow flexors, wrist extensors, finger spreaders, thumb abductors and adductors (all MRC 4) on both sides, and weakness of the muscles in both legs (MRC 4 proximally, MRC 4 distally on the right side and MRC 3 on the left side) were found. Reflexes were decreased in the arms and absent in the legs. Vital capacity was normal. Concentric needle EMG revealed widespread denervation and reinnervation in arms, legs and in the thoracic region. Since 1990, the disease course has been gradually progressive.
Group 2 (symmetrical and distal weakness of both arms and legs)
In 1982, a 27-year-old woman noticed dragging of both feet while walking and fasciculations in both legs at rest. In 1992, writing became impaired. In 1998, neurological examination showed distal atrophy of both legs. Muscle strength was decreased in finger spreaders, ankle dorsiflexors, ankle plantarflexors, toe flexors and extensors (all MRC grade 4). Reflexes were normal except for absent ankle reflexes on both sides. Vital capacity was normal. Concentric needle EMG revealed signs of denervation and reinnervation in both legs and signs of reinnervation in the right distal arm. Nerve conduction studies showed decreased CMAP-amplitudes in the leg nerves. Since 1982, the disease course has been gradually progressive, but signs and symptoms have remained localized distally in the limbs.
Group 3a (asymmetrical and distal weakness of arms)
In 1976, a 30-year-old man slowly developed weakness of his right wrist and finger extensors. He noticed fasciculations and cramps in his right forearm and his writing deteriorated. Surgery to the right radial nerve in 1986 did not lead to improvement. Neurological examination in 1998 showed distal atrophy of the right arm and weakness of the wrist extensors (MRC grade 3), finger spreaders, finger extensors and thumb abductors and adductors (grade 4). Reflexes were decreased in the right arm. Vital capacity was normal. Concentric needle EMG revealed signs of reinnervation in the right arm distally. Since 1990, signs and symptoms have been stationary.
Group 3b (asymmetrical and proximal weakness of arms)
In 1988, a 60-year-old man noticed difficulty with handling cutlery and picking up objects above eye level with his right arm. In 1997, proximal weakness of his left arm developed. He also noticed cramps in both arms. Neurological examination in 1998 revealed atrophy in both shoulder girdles, proximal arms and hands, and fasciculations in the right shoulder girdle. Weakness was found in the shoulder abductors (MRC grade 2 at the right and grade 4 on the left side), elbow flexors and extensors, wrist extensors, finger extensors, finger spreaders and thumb abductors on the right side (all grade 4). Areflexia was observed in all four limbs. Vital capacity was normal. Concentric needle EMG revealed signs of denervation and reinnervation in the proximal arms, in the thoracic region and in one leg distally. Since 1998, proximal weakness in both arms has been progressive, leading to increasing impairments in ADL, such that he has needed assistance in washing and dressing since 2001.
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Discussion |
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We describe the clinical and electrophysiological characteristics of 49 patients with sporadic, adult-onset LMND. In contrast to previous studies, patients were selected on the basis of negative DNA tests and the absence of conduction block or other demyelinating features on extensive nerve conduction studies. Moreover, all patients had a disease duration more than 4 years in order to exclude the majority of patients with ALS. On the basis of our findings, we propose to classify patients with sporadic adult-onset LMND as follows: (i) slowly progressive SMA; (ii) distal SMA; (iii) segmental distal SMA; and (iv) segmental proximal SMA. The clinical characteristics of these subgroups are discussed in relation to previous studies (see review in Table 5).
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Slowly progressive SMA (group 1)
After a median disease duration of 11 years, these patients had generalized and severe weakness. Five patients had a vital capacity below 80%, but only two of them had signs and symptoms of respiratory insufficiency after a disease duration of 11 and 27 years, respectively. It was previously considered that most patients who present with LMN signs would eventually develop ALS, because progression is rapid and UMN signs appear; only patients with slow progression of pure LMN signs should be diagnosed as progressive SMA (Müller, 1952
; Norris, 1991). To differentiate patients with a slowly progressive disease course, as included in our study, from patients with a disease course similar to that of ALS, we propose to classify these patients as slowly progressive SMA. The asymmetrical onset of signs and symptoms found in our patients, and the symmetrical spread of symptoms later in the disease, have been described previously (Harding et al., 1983). Our patients with slowly progressive SMA often showed more severe weakness in the legs than in the arms. Müller also found that weakness in the legs only was much more common in patients with progressive SMA than in patients with ALS and progressive bulbar palsy (Müller, 1952). This could not be confirmed in other more heterogeneous groups of patients (Meadows et al., 1969b; Harding et al., 1983; Chio et al., 1985). These studies included patients with non-generalized disease forms or patients with MMN, who have more pronounced weakness in the arms (Van den Berg-Vos et al., 2002). In our study, the age at onset of slowly progressive SMA was comparable with the age at onset of ALS. Previous studies reported an earlier onset of progressive SMA (Müller, 1952; Harding et al., 1983; Norris 1991), which may be explained by the inclusion of patients with MMN, in whom the disease often starts in the second or third decade. Interestingly, an M-protein was found in three of our patients with slowly progressive SMA (23%). Although the occurrence of serum M-protein increases with age and the number of patients was small, this could suggest an association between plasma cell dyscrasia and slowly progressive SMA as has been described previously for both progressive SMA and ALS (Shy et al., 1986).
Distal SMA (group 2)
Sporadic cases with symmetrical and distal muscle weakness in both arms and legs, like the majority of our patients in group 2, have usually been described under the heading of hereditary distal SMA (Meadows and Marsden, 1969; Meadows et al., 1969a; McLeod and Prineas 1971; Harding and Thomas, 1980a). However, Harding and Thomas found that of all 78 patients described in the literature, including their own series, only 29 patients showed an autosomal dominant and eight patients an autosomal recessive inheritance; 41 patients (52%) represented sporadic cases (Harding and Thomas, 1980a). Although genetically heterogeneous and with an age at onset ranging from 5 to 70 years (Serratrice, 1983), the clinical presentation of distal SMA is fairly homogeneous. Slowly progressive symmetrical muscle weakness and atrophy affect the legs and feet first. Years later, the hands and the forearms are affected. Distal SMA should be differentiated from hereditary motor and sensory neuropathy (HMSN) type 2, the axonal variant of Charcot–Marie–Tooth disease, in which clinical sensory loss is not always present (Harding and Thomas, 1980b). Features which distinguish between distal SMA and HMSN type 2 are more common upper limb weakness (Harding and Thomas, 1980a) and low or absent sensory action potentials in HMSN type 2 (Harding, 1993). In our eight patients, the results of the sensory examination were normal, both clinically and electrophysiologically. In group 2 in particular, electrophysiological analysis showed evidence of a more generalized disease pattern, with subclinical involvement of the upper and middle lumbosacral regions.
Segmental distal SMA (group 3a)
The clinical presentation of muscular atrophy and weakness in the hand and forearm of the patients of group 3a was first described by Hirayama (Hirayama et al., 1963), who proposed the term juvenile muscular atrophy of unilateral upper extremity. Later, he replaced unilateral by distal, when about 33% of patients were found to have less pronounced contralateral weakness of the hand and forearm (Hirayama, 1972; Hashimoto et al., 1976). Both Hirayama and others reported that the deltoid, biceps and triceps brachii muscles could be affected and that reflexes could be brisk in the affected arm (Hirayama et al., 1963; Sobue et al., 1978). Proximal weakness in the ipsilateral arm and distal weakness in the contralateral arm, together with brisk reflexes, were also found in 21 and 29% of our patients, respectively, who were all caucasian, in contrast with those described by Hirayama. This demonstrates that the disease progresses to adjacent spinal cord segments and, therefore, we suggest the term segmental distal SMA. In addition, abnormalities on concentric needle EMG were found in lower limb regions in 
33% of patients, suggesting an even more widespread disease of the spinal cord. In one of our patients, atrophy and an increased signal intensity of the cervical spinal cord at the level C3–C4 were found, which may represent focal corticospinal tract damage of unknown pathogenesis, and has also been described by others (Nogues, 2000). We found an older age at onset and a higher proportion of women to be affected than in other studies. Nevertheless, these patients appeared to have a relatively benign disease form as symptoms and signs were still confined to two limb regions after a median disease duration of 16 years. The notion that Hirayama disease could also occur in women and older patients is important for clinical practice.
Segmental proximal SMA (group 3b)
The phenotype of asymmetrical proximal weakness in the arms in the patients of group 3b is less well known. Patients with ipsilateral muscle weakness and wasting in shoulder and proximal arm muscles have been previously described (Kaeser et al., 1983; Katz et al., 1999); after years, this progressed to the contralateral shoulder in a majority and, to the lower limb and neck muscles, in a minority of patients. A similar mode of disease progression with involvement of adjacent spinal cord segments was found in the majority of our patients. In one patient, mild leg weakness developed after a disease duration of more than 20 years. These findings not only suggest widespread involvement of the cervical anterior horn cells, but also of motor neurons in the thoracic and lumbosacral regions. Concentric needle EMG revealed abnormalities in thoracic and leg muscles. The proximal weakness measured in the first affected arm was often relatively severe and comparable with that seen in the patients with slowly progressive SMA (Table 3) and resulted in a man-in-the-barrel phenotype (Hu et al., 1998; Katz et al., 1999) in two of our patients. The striking male predominance that we found is comparable with that described by Kaeser and colleagues (Table 5) (Kaeser et al., 1983). In addition, Hu and colleagues also found a male:female ratio of 9:1 in the subgroup of ALS patients with a man-in-the-barrel phenotype (Hu et al., 1998). Although this form of LMND appears to carry a favourable prognosis (Kaeser et al., 1983), it nevertheless may cause considerable functional impairment in ADL. One patient in each of the subgroups 3a and 3b demonstrated weakness in one leg only, and the weakness remained localized to this leg for years. These patients could also be categorized under the heading of monomelic amyotrophy of lower limb, a disease form that is most often reported in India (Prabhakar et al., 1981; Gourie-Devi et al., 1984).
In the different types of LMND described in this study, most of the affected patients were male. The male to female ration of 4:1 in our study is comparable with the ratio of 6:1 described in the literature (Table 5). This suggests that not yet identified genetic or hormonal factors play a role in the pathogenesis. Importantly, after a disease duration with a median of 12 years for the whole group, the majority of patients of group 1 with the generalized disease form still had no respiratory symptoms and the patients of groups 2 and 3 with non-generalized disease forms were still relatively mildly affected without respiratory insufficiency. Retro spectively, the prognosis of sporadic LMND with adult onset thus seems to be relatively good. The clinical phenotypes of the different subgroups described in this study may help to differentiate the several LMND forms from each other. However, at present it is not known how long patients have to be observed before the diagnosis LMND can be made with certainty. Prospective studies are needed to investigate whether specific clinical or pathogenic variables may help to identify patients with a more benign form of LMND.
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Acknowledgement |
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This study was supported by a grant from the Prinses Beatrix Fonds. The research of L.M.V.d.B. was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences.
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References |
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