Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Monomelic amyotrophy: Clinical profile and natural history of 279 cases seen over 35 years (1976–2010) Atchayaram Nalini, Mandavilli Gourie-Devi, Kandavel Thennarasu & Aravinda Hanumanthapura Ramalingaiah To cite this article: Atchayaram Nalini, Mandavilli Gourie-Devi, Kandavel Thennarasu & Aravinda Hanumanthapura Ramalingaiah (2014) Monomelic amyotrophy: Clinical profile and natural history of 279 cases seen over 35 years (1976–2010), Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15:5-6, 457-465, DOI: 10.3109/21678421.2014.903976 To link to this article: http://dx.doi.org/10.3109/21678421.2014.903976

Published online: 22 May 2014.

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Date: 12 July 2017, At: 20:33

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014; 15: 457–465

ORIGINAL ARTICLE

Monomelic amyotrophy: Clinical profile and natural history of 279 cases seen over 35 years (1976–2010)

ATCHAYARAM NALINI1, MANDAVILLI GOURIE-DEVI2, KANDAVEL THENNARASU3 & ARAVINDA HANUMANTHAPURA RAMALINGAIAH4 1Departments

of Neurology, 3Biostatistics, and 4Neuro Imaging and Interventional Neuroradiology, National Institute of Mental Health and Neurosciences, Bangalore, and 2Institute of Human Behaviour and Allied Sciences, New Delhi, India

Abstract Our objective was to study the clinical characteristics and natural history of monomelic amyotrophy (MMA). We used a retrospective study of 279 patients diagnosed to have either upper (Hirayama disease) or lower limb MMA. Results showed that brachial MMA (BMMA) occurred in 224 patients (male:female, 9:1). Mean age of onset was 19.5  4.18 years. Progression occurred over less than five years in the majority (95.9%) of patients. Duration at the last follow-up was: up to five years in 61.4%, 5–10 in 21.3%, 10–15 in 7.2%,  15 years in 10.1%. MRI showed asymmetrical lower cervical cord atrophy in 44.6% of patients. Crural MMA (CMMA) occurred in 55 patients (male:female, 13:1). Mean age of onset was 21.38  5.3 years. Similar to BMMA, most cases (65.5%) had onset between 15 and 25 years of age. Total duration of illness at the last follow-up was up to five years in 52.7%, 10 and beyond in 47.3%. In conclusion, a large cohort of patients with monomelic amyotrophy seen over 35 years (1976–2010) is described. Study data support the clinical findings and its natural history with long term follow-up, and the findings emphasize that monomelic amyotrophy is a ‘benign’ condition with a self-limiting course. Key words: Monomelic amyotrophy, brachial, crural, Hirayama disease, natural history, India

Introduction In 1959, Hirayama described the clinical entity of atrophy of a single upper limb and characterized its clinical features (1,2). Gourie-Devi et al. in 1984 reported on single upper or lower limb atrophy and coined the term ‘monomelic amyotrophy’ (MMA) (3). Later, the terms brachial monomelic amyotrophy (BMMA) and crural monomelic amyotrophy (CMMA) were suggested by the present authors (4,5). Other names assigned for this disorder are ‘Hirayama disease’, ‘monomelic spinal muscular atrophy’ and ‘non-progressive juvenile spinal muscular atrophy in juvenile and young adults’ (6,7). Most cases are described from Asian countries (1,2–5,7–16); however, small series have been reported from the West (17–23). Characteristic features of BMMA include young age of onset, sporadic occurrence, male preponderance, weakness and atrophy affecting intrinsic muscles of hand and forearm

muscles and usually confined to a single limb (2,3,5). Infrequently symptoms of cold paresis and hyperhydrosis are described with abnormal sympathetic skin response (24). In CMMA the leg muscles are predominantly affected with clinical features similar to BMMA (10,23,25–29). We evaluated 279 cases of MMA, and we present here the clinical, electrophysiological and imaging findings and the natural history of disease progression.

Materials and methods This was a retrospective study of patients diagnosed with BMMA and CMMA, who were seen between 1976 and 2010. All subjects had given written informed consent to undergo clinical examination and laboratory procedures as part of the evaluation process. Institutional ethics committee approval was obtained for the collection of data. Medical records were

Correspondence: A. Nalini, Department of Neurology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560029, India. Fax: 91 80 26564830. E-mail: [email protected] (Received 20 October 2013 ; accepted 9 March 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.903976

458 A. Nalini et al. meticulously scrutinized and all the details of neurological history, findings and investigation results documented. Every patient was clinically evaluated by a neurologist (MGD/AN) and investigations including routine haemogram, blood chemistry and serum creatine kinase were performed. Concentric needle electromyography (EMG) of distal and proximal muscles in affected upper limb(s) and one unaffected limb was performed in most of the cases. Motor and sensory conduction studies of affected limb, contralateral limb and one unaffected limb were performed. Data were analysed using SPSS version 15.0 and results were generated using descriptive statistics such as mean  standard deviation, median and range for continuous variables and frequency (%) for categorical variables. Age of onset, gender, duration of illness and period of progression were compared with the severity of disability. Electromyography (EMG) and nerve conduction studies In BMMA the muscles tested were biceps brachii, first dorsal interossie and/or abductor digiti minimi, quadriceps/tibialis anterior; in CMMA, the muscles were quadriceps, tibialis anterior, biceps brachii or extensor digitorum communis. Paraspinal muscles were not tested. Conduction studies of median, ulnar, common peroneal and sural nerves were performed. MR imaging protocol MR imaging of cervical or lumbosacral region was carried out on 1.5T (Siemens, Magnetom vision) and 3T (Philips, Achieva) MRI systems. T1, T2 axial and T1 sagittal sections with 3-mm slice thickness were made, including post contrast T1W imaging. For BMMA flexion, studies were performed using the same protocol. CT myelography performed in 31 of the 224 patients had revealed focal atrophy prominently noted at C5,6 levels. Delayed contrast study had not revealed any cavity. Nine (BMMA, 6; CMMA, 3) of these cases have been reported earlier (30). Follow-up evaluation All the patients were sent simple questionnaires in English and local languages along with return paid envelopes to obtain necessary information for the assessment of clinical status and disability. Response was received from 79 cases of BMMA and 16 cases of CMMA. Questionnaire data were included along with the retrospective details for final assessment of above mentioned parameters. Finally, 207 cases of BMMA and all 55 cases of CMMA had at least one follow-up. Results Over a period of 35 years, 279 patients were diagnosed with MMA (BMMA, 224; CMMA, 55).

During the same period, 2462 cases of chronic anterior horn cell disorders including ALS, MMA and Madras Motor Neuron Disease (MMND) (31) were evaluated. MMA (279/2462) formed 11.3%, and MMND (130/2462) 5.3% of the total cases. Brachial monomelic amyotrophy (BMMA) Affected limb. The neurological features are summarized in Table I. Age of onset is depicted in Figure 1. Mean duration of illness was 46.7  61.1 months (median, 27; range 6–504) (Figure 2). Neurology consultation was sought within the first two years of onset in 122 (54.4%) patients, and within the first five years in 180 (80.4%) patients. In 197 (87.9%) patients, the illness had a progressive course, while in 27 (12.1%) the deficits remained stable after its detection. The disease progressed for up to five years or less in 95.5% of the patients. They attained a stable state at specified time-points (by one year in 45.1%, two years in 21.8%, three in 15.7%, four in 11.6% and five in 1.5%). In the remaining 4.1% of patients, stable state was attained after five years (at the end of six years in four patients and at nine and 10 years in one each). Atrophy and weakness predominantly involved the small muscles of hands, the forearm flexors and the extensors. Mild proximal muscle wasting was noted in 42.8% of the patients. Isolated proximal muscle involvement occurred in eight cases. Degree of atrophy was assessed subjectively and reported to be mild in 7.1% of the patients, moderate in 66.1% and severe in 28.6%. Muscle strength was graded as per Medical Research Council grading system. Distal weakness corresponding to C7, C8, T1 segments was present in 91.1% of the patients (mild in 21.4%, moderate in 54.0% and severe in 24.6%). Muscle bulk of brachioradialis was totally/relatively spared in 63.1% of 130 cases. This information was not recorded in the remaining cases. Around 64.2% had fasciculations and 84.8% had minipolymyoclonus. Hyperhydrosis of the palm and sensation of coldness in the hand was reported in 18.3%. Numbness was reported in 8.0% and vague pains in the limb in 22.8%. Thirteen patients reported mild and inconsistent impairment to pinprick sensation over C8, T1 distribution. Normal tone was present in 78.1% and hypotonia in 21.9% of patients. Deep tendon reflexes were generally normal to hypoactive, but pathologically hyperactive biceps, supinator and triceps reflexes were also observed (Table I). Hoffmann’s sign was not present in any case. Cranial nerves, cerebellar, extrapyramidal and sensory examinations were normal. Knee and ankle jerks were normal in 60.5%, hypoactive in 23.8% and pathologically brisk in 15.7% of patients. However, there was no spread or presence of clonus or Babinski’s sign. Contralateral upper limb. Thirty patients had involvement of the contralateral limb at the time of first

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Table I. Clinical features of 224 patients with brachial monomelic amyotrophy (BMMA) and 55 patients with crural monomelic amyotrophy (CMMA). (Where percentage is not applicable the expression is indicated beside the variable). Characteristics

BMMA n  224 (%)

CMMA n  224 (%)

Age at presentation (years) Age at onset (years) M: F Duration of illness (months) Period of progression (months) At last follow-up Duration of illness (months) Period of progression (months) Stationary phase (months) Illness noted by Self Others Involvement of extremity RUL LUL RLL LLL Pain in affected limb Cold paresis Cramps (in atrophic muscles) Wasting Distal only Proximal only Predominantly distal Weakness Distal Proximal only Predominantly distal Deep tendon reflexes Affected limb Absent/hypoactive Normal Hyperactive Pathologically hyperactive Contralateral limb Absent/hypoactive Normal Hyperactive

23.5  6.4 19.5  4.1 (13 –33) 9:1 46.7  61.1 (6 – 504) 24.2  18.6 (1–120)

25.6  6.5 21.4  5.3 (9 –33) 13:1 52.4  52.5 (10 –240) 27.9  21.5 (3 – 84)

77.1  87.8 25.0  21.3 76.3  90.6

81.4  68.1 28.5  22.6 79.6  59.3

208 (92.9) 16 (7.1)

34 (61.8) 21 (38.2)

140 (62.5) 84 (37.5) – – 51 (22.8) 116 (51.8) 35 (15.6)

– – 29 (52.7) 26 (47.3) 45 (81.8) – 9 (16.4)

116 (51.8) 8 (3.6) 100 (44.6)

8 (14.5) 6 (10.9) 41 (74.5)

204 (91.1) 8 (3.6) 96(70.1)

8 (14.5) 6 (10.9) 41 (74.5)

83 100 38 3

31 13 10 1

(37.0) (44.6) (17.0) (1.3)

53 (23.7) 136 (60.7) 35 (15.6)

(56.4) (23.6) (18.2) (1.8)

3 (5.4) 42 (76.4) 10 (18.2)

All values are measured as mean  SD. RUL: right upper limb; LUL: left upper limb; RLL: right lower limb; LLL: left lower limb; M: males; F: females.

Figure 1. Bar diagram shows mean age at onset of illness in BMMA. The majority of patients had onset between 15 and 25 years of age.

460 A. Nalini et al.

Figure 2. Depicts duration of illness at presentation in BMMA. Most had presented within two years of onset of illness.

evaluation (mild wasting in 18.8%; mild weakness in 51.5%, moderate in 11.9%). Minipolymyoclonus was present in 34 patients. Tone was reduced in 2.7% and was normal in the remaining cases. Electroneuromyography Affected limb. EMG was performed in 200 patients. The atrophic small muscles of the hand showed evidence of fibrillations in 71.0%, fasciculations in 96.5% and large/giant motor unit potentials (MUPs) in 80.5% of patients. When involved, biceps muscle revealed fasciculations and large amplitude MUPs. Conductions of median and ulnar nerves revealed reduced amplitude of compound muscle action potential (CMAP) in 9.0% of patients. Mean amplitude for ulnar nerve was (5.06  3.21 mv (range, absent evoked motor response (EMR) to 13.6 mv)); for median nerve (8.96  4.7mv (range, absent EMR to 21.7 mv)). Contralateral limb. EMG (n  194) showed abnormalities in 21.1% of patients. There were occasional fibrillations in 51.2%, fasciculations and large amplitude MUPs in 85.3%. CMAP of ulnar nerve was (8.36  3.11 mv (range 0.71–12.5 mv); median nerve (9.37  3.08 (range 1.66–14.5 mv)). Thus, muscles supplied by C8,T1 segments were more affected. There was no evidence of conduction block. Distal motor latencies, conduction velocities and sensory nerve action potentials were normal in both limbs. Common peroneal and sural nerves revealed normal findings. MR imaging results Cervical spine imaging was available in 110 cases. Abnormalities were detected in 56 cases. They comprised – in neutral position 1) abnormal (straight or kyphotic) cervical curvature in 60.7%; 2) localized cord atrophy extending from C5 to T1 level in 44.6%

(asymmetrical in 68.0%). Cord atrophy was most prominent at C5–6 level in 40.0% and at C6–7 in 28.0% (Figure 3); 3) asymmetrical/symmetrical non-compressive intramedullary high intensity signals were identified in 16.1% (C3 through C7), but most prominently noted at C5–6 and C4–5 levels. ‘Owl’s eye’ or ‘eye of the snake’ appearance was noted in nine cases, which on T2 weighted imaging revealed focal high intensity areas corresponding to anterior horn cell region involvement. This feature is typically described in spinal cord infarction (40,41). Primary cervical canal stenosis was observed in four patients. T1W contrast MRI in flexion carried out in 20 cases demonstrated forward displacement of cervical cord in eight cases only. Twelve patients had loss of attachment between the posterior dural sac and subjacent lamina (Figure 4). Disability Disability was scored as mild, moderate and severe based on subjective motor impairment. Occupation and dominant limb affection had a significant bearing on the degree of disability. The groupings were based as follows: • Mild: motor functions minimally affected, but patient is able to carry on with all activities of daily living and occupation without any assistance. • Moderate: motor functions moderately affected; patient requires assistance to carry out certain activities of daily living. • Severe: patient is forced to perform motor tasks with the contralateral upper limb or is compelled to change job. Disability was reported in 97.0% of the patients; transfer of skills to the opposite limb occurred in 17.0%, and change of occupation in 6.9%.

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Figure 3. (A) Sagittal T2W image of the cervical spine shows spinal cord atrophy and focal hyperintensity of the cord secondary to gliosis. (B) Axial T2W image shows asymmetric cord atrophy with right half of the cord showing more pronounced volume loss. (C) Axial T2W image at the level of signal change shows volume loss and gliosis.

A comparison between the age of onset, gender, duration of illness and period of progression with severity of disability showed no significant relationship. Final evaluation Total duration of illness was calculated as on last follow-up for 207 cases (hospital and questionnaire data). A large number (61.4% of 207) had a minimum total duration of five years, 21.3% between five and 10 years, 7.2% between 10 and15 years, and 10.1% more than 15 years. At last follow-up the progression of symptoms had occurred up to 12 months in 36.6%, 13–24 in 17.9%, 25–36 in 12.5%, 37–48

in 8.0%, 49–60 in 1.3% and more than 60 months in 4.5%. Only one patient reported progression of up to 10 years. In 19.2% of the cases there was no progression. Thus, the disease progressed for up to five years or less in 95.5% of patients. The maximum follow-up was 25 years and that particular patient had experienced a transient second phase of progression after 21 years of stationary period and was compelled to give up his tailoring work. Among the 79 patients who returned the completed questionnaire, the long-term follow-up period was 84.15  87.6 months (median, 52.0; range 3–330). Seventy-two patients had no change in the deficits and had a stationary period of 50.61  53.25 months (median, 35.0; range 0–312). It is important

Figure 4. (A) Dynamic MRI of cervical spine. a) sagittal T1W image of the cervical spine shows cord atrophy. (B) Sagittal T1W images in flexion reveal prominent posterior epidural space.(C) Post contrast sagittal T1W image in flexion shows strong homogenous enhancement of the posterior epidural space.

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to note that none of the patients evolved into the generalized form of spinal muscular atrophy, nor did any patient with the presence of pathological hyperactive reflexes evolve into amyotrophic lateral sclerosis. Crural monomelic amyotrophy Affected limb. The neurological deficits are summarized in Table I. Of the 55 patients, 51 (92.7%) were males and the mean age of onset was 21.38  5.3 years (9–33). In most cases (65.5%) onset was between 15 and 25 years. Mean duration of illness at the time of evaluation was 52.4  52.5 (median, 36.0 months; range 10–240). Neurology consultation was sought within the first two years after onset in 26 (47.2%) cases, and within the first five years in 44 (80.0%). Wasting and weakness were progressive at the time of presentation in 32 (58.1%) patients. The stationary phase in the remaining 23 (41.8%) cases was 69.52  53.17 months (2–180). Thus, in more than one-third (41.8%) of the patients, the atrophy was fortuitously noticed. Mean period of progression was 27.9  21.5 months (3–84) and it lasted up to two years in 20 (62.5%), and up to five years in 11 (20%) patients. Only one patient progressed beyond five years. Fasciculations in atrophic muscles were reported in 17 (30.9%), and calf muscle cramps in nine (16.4%) patients. Leg muscles were prominently affected in 49 (89.1%) patients. Thigh muscle wasting was global in 47 (85.5%) and was mostly identified during examination. Degree of distal wasting was mild in 12 (21.8%), moderate in 34 (61.8%) and severe in nine (16.4%) patients. Tone was normal in 45(81.8%) and hypotonic in 10 (18.2%) patients. Weakness was mild and present in 33 of the 49 cases (67.3%). Knee and ankle jerks were normal in 13 (23.6%), hypoactive in 31 (56.4%) and pathologically brisk in 10 (18.2%) without any spread. Plantar response was flexor in all the patients. Contralateral limb. Wasting or weakness was not detected in the contralateral limb. Normal tone was observed in 53 (96.4%) cases and hypotonia in two (3.6%). Tendon reflexes were normal in 42 (76.4%), hypoactive in three (5.4%), and pathologically brisk in 10 (18.2%) patients. Babinski’s sign was not noted in any case.

Electroneuromyography and MR imaging EMG was performed in 40 (72.7%) patients. The atrophic muscles revealed fibrillations in 13 (32.5%), suggestive of active denervation, fasciculation potentials in 38 (95.0%) and giant MUPs in 34 (85.0%), suggestive of chronic partial denervation with reinnervation. Common peroneal nerve revealed reduced CMAP amplitude in three (7.5%) cases while distal latencies and conduction velocities were normal. Conduction studies of sural nerves were normal. MR

imaging of the lumbosacral cord performed in 16 cases was normal. Final follow-up evaluation Duration of illness among the 55 cases was less than five years in 29 (52.7%), 5–10 in 11 (20.0%), 11–15 in 11 (20.0%) and more than 15 years in four (7.3%) patients. The 16 patients who returned the completed questionnaire had a follow-up between five and 20 years. The period of progression at last follow-up for the 55 cases was: up to 12 months in 16 (47.0%), 13–24 in five (14.7%), 25–36 in four (11.8%), 37–48 in two (5.9%), 49–60 in five (14.7%) and more than 60 in two (5.9%).Thus, in the majority of patients the illness evolved over less than two years. Discussion The proportion of monomelic amyotrophy among patients with motor neuron disease and its variants was 11.3% (279/2462). It is reported to range from 8% to 29% in other hospital series from India (3,32,33). Brachial MMA The clinical profile and long-term follow-up in the largest series of patients with BMMA is described here. More than 200 cases are reported from India (3–5,10,11,34,35), while small series are published from the West (17–23,36). Most series consist of sporadic cases, except for a few describing the familial form (37–39). The first report on this rare entity emerged from Japan (1). The classical features consist of onset in late second or early third decade with atrophy and weakness affecting predominantly the distal muscles of a single limb (2,6,8,9,21,23,36). In our series, 40% had associated asymptomatic/symptomatic proximal muscle wasting. Peiris et al. have reported involvement of shoulder girdle muscles in five of 102 patients (12), while Hirayama et al. reported one patient each with involvement of pectorals and triceps brachii out of their 20 cases (3). Thus, proximal muscle affection was more frequently observed in our series. In more than 90% of cases, the period of progression of motor deficits before stabilization, ranged from one to four years. At last follow-up, only 4.5% had progressed beyond five years, and it was noteworthy that this group did not develop greater disability. Thus, it is evident from our large series that a longer period of progression did not alter the prognosis. Previous authors also mention an illness progression over two to four years (2–7,12), but with a higher percentage (range 12.7–50%) with progression beyond five years (2, 9,12). About one-fifth of our patients had a follow-up of more than 10 years and none (except one) had

Monomelic amyotrophy and its natural history late progression. It may be emphasized here that none of our patients evolved into ALS or spinal muscular atrophy over time. Thus, a consistent observation is that most of our patients had a favourable outcome and the majority (80%) had good functional capacity. It is important to note that a small number of the patients who were manual labourers and computer operators experienced significant disability. Barontini et al., in a longitudinal study of 13–15 years, showed findings comparable to the present series (40). Transient worsening of weakness and motor abilities of affected hand on exposure to a cold environment is termed as cold paresis (24). More than half of our patients experienced this symptom and it appears to be a sensitive clinical marker for diagnosis of BMMA (38,39). This feature is not described in patients with other forms of chronic anterior horn cell disorders. Autonomic disturbances are suggested to be the cause for this symptom. Interestingly, few of our patients hailing from cold regions in India experienced cold paresis for many months to years before the onset of atrophy (34,35). In our earlier study, we demonstrated abnormal sympathetic skin response in BMMA (24). Although most of our patients demonstrated hypoactive to normal stretch reflexes, a small number had pathologically hyperactive reflexes in all four limbs. Babinski and Hoffmann signs were distinctly absent. Thus, in this large series, hyperactive DTRs was the only evidence suggestive of pyramidal tract dysfunction in certain cases, but this did not augur an evolution into ALS during long-term follow-up. Similarly, in earlier reports, stretch reflexes were noted to be normal in upper limbs and rarely increased in lower limbs (2,3,5,7,34). In the large series reported by Peiris et al., reflexes in upper limbs were absent or hypoactive (12). In the series reported by Hirayama et al., reflexes in upper limbs were normal to hypoactive with mild asymmetry, and 40% of 20 patients had moderate to very hyperactive reflexes in the lower limbs (2). In a minority ( 20%) of our patients, the deficit was bilateral, but gross asymmetry persisted even at the last examination, i.e. at the end of 10–15 years. The first affected limb was always more severely affected. Presence of contralateral limb atrophy is reported to range from 33.8% to 61.8% in different series, but gross asymmetry was a consistent feature (9,10,12,15). EMG of the atrophic limb showed varying degree of neurogenic changes and, in 20%, the contralateral limb also showed evidence of neurogenic changes in the affected muscles. Similar findings have been reported earlier with presence of bilateral abnormalities in as high as 57.0% of patients (2,3,5–7,12). Asymmetrical atrophy of the lower cervical segments was the most prominent abnormality noted on imaging. Many had abnormal cord signal changes, which is termed the ‘owl’s eye’ or ‘snake

463

eye’ appearance and this corresponds to the anterior horn cell (AHC) region. These are small intramedullary high signal intensities generally demonstrated in cases of cervical spondylosis or ossification of the posterior longitudinal ligament. This is postulated to depict cystic necrosis of the grey matter with significant anterior horn cell loss secondary to mechanical compression and venous infarction (41,42). As the abnormal signal changes observed in BMMA have a close resemblance to ischaemic myelopathy, it could be ascribed to local ischaemia of AHCs, triggered by anterior shifting of the posterior cervical dura upon neck flexion. This finding suggests that compression could be a possible aetiology among other unknown factors in the causation of BMMA. In an earlier report, a high percentage (49% of 47 patients) had demonstrated atrophy of the lower cervical cord as the major abnormality (46). Other authors have also reported this feature as a common finding (43–45,47). Forward displacement and anteroposterior flattening of cervical cord is presumed to be the most important pathogenic mechanism and is emphasized in many reports, but its aetiology and time of occurrence are not clear (46,48). In our series, only a small percentage of cases demonstrated this classical feature. In the study by Hirayama et al., and Huang et al., a high percentage of patients (87% of 47) and (95% of 40), respectively, demonstrated this finding (45,47). However, other studies have not confirmed the finding (47,49,50). Interestingly, this phenomenon is said to be particularly present during the progressive phase of the disease (46). As most of our patients had attained the stabilized phase at the time of imaging, this could have been a possible reason for its absence in many of our clinically classical cases of BMMA. It may be pertinent here to raise the question as to how an anatomical abnormality of a fibrous structure like the dura mater would alter with the different phases of evolution of the disease. Furthermore, it is intriguing to note that forward displacement of the dura has been described in normal individuals also, raising doubts about its major contribution in the aetiopathogenesis of BMMA (34,49). Thus, the precise aetiology of BMMA may still be elusive. However, in the absence of flexion induced myelopathy, presence of asymmetric lower cervical cord atrophy is considered to be a characteristic finding (43,46). Primary cervical canal stenosis (PCCS) was observed in four cases. Their total duration ranged from eight to14 years. None had the other described features of PCCS such as chronic pain, regional anaesthesia or bilateral deficits. It is likely that PCCS could also be a conceivable cause, leading to focal AHC ischaemia induced by neck flexion. An attempt was made to compare age of onset, gender, duration of illness and period of progression with the severity of disability, but no significant relationship was observed.

464 A. Nalini et al. Certain limitations acknowledged by the authors are that this was a retrospective analysis and electrophysiological and imaging studies were not performed in all cases. Further, all cases did not have follow-up. Crural MMA All cases had wasting of the leg muscles with minimal weakness. A few cases had foot drop. None had intrinsic foot muscle involvement. The thigh muscles were wasted in a significant number (80%), but without associated weakness, and most patients were unaware of this deficit. In 40% of the patients, the deficit was identified by others, which prompted the patients to consult a neurologist. In contrast to ours, in other series both anterior and posterior crural muscles were involved, while intrinsic foot muscles were less frequently affected (25–27). Unlike BMMA, only a few reports exist on lower limb amyotrophy (3,23,25–29). Under the eponym of ‘wasted leg syndrome’, 40 patients from India were evaluated clinically and by electrophysiological studies. Selective involvement of leg and quadriceps muscles occurred in 90%, global involvement in 65%, and isolated atrophy of quadriceps in 12.5% of patients (25). There was no case with isolated quadriceps involvement. De Freitas et al. had observed wasting of the entire limb in six of their 16 patients (23). Di Muzio et al. have reported on six cases of single lower limb amyotrophy with benign outcome (28). The mean age at onset in the present series was 21 years. De Freitas et al. have reported a median age of onset of 20 years. Unlike BMMA, in the majority the illness progressed over less than two years and not more than four years, and the deficit was strictly confined to a single limb. Previous reports also mention progression of deficits for not more than four years (23,25–28). In the presence of foot drop, patients experienced exertion-induced fatigue and minimal disability. A small percentage of the patients had pathologically hyperactive reflexes in the lower limbs. Nevertheless, no patient developed any serious form of anterior horn cell disorder on long-term follow-up. This feature is not reported by other authors. Chronic neurogenic changes on EMG were confined to the atrophied muscles of the affected limb, except for four cases where the patients showed abnormality in the opposite limb. De Freitas et al. had found fibrillations and positive discharges in addition to chronic denervation and reinnervation in the affected limb and also chronic denervation potentials in the opposite limb (23). Lumbosacral (LS) MRI did not show any cord abnormalities in our patients. Other authors have also reported normal findings on LS MRI (23,28). Thus, unlike the presence of MRI findings in BMMA, no abnormalities were observed in CMMA.

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