Handbook of Clinical Neurology, Vol. 82 (3rd series) Motor Neuron Disorders and Related Diseases A.A. Eisen, P.J. Shaw, Editors © 2007 Elsevier B.V. All rights reserved Chapter 11 Monomelic amyotrophy of upper or lower limbs M. GOURIE-DEVI* Institute of Human Behaviour and Allied Sciences, and Department of Clinical Neurophysiology, Sir Ganga Ram Hospital, New Delhi, India 11.1. Introduction Monomelic amyotrophy in which neurogenic atrophy is restricted to one limb is a heterogenous disorder, involving one upper or lower limb. Insidious onset of atrophy and weakness, presumed to be due to anterior horn cell involvement, starting in the second or third decade with male preponderance and sporadic occur- rence are the characteristic features. Progression is slow and followed by stabilization within a few years, result- ing in a benign outcome. Cranial nerves, pyramidal, sensory, cerebellar and extrapyramidal systems are not involved. Hirayama et al. (1959) from Japan reported atro- phy of a single upper limb and labeled it as “juvenile muscular atrophy of unilateral upper extremity.” Prabhakar et al. (1981) from India reported atrophy of muscles of one lower limb and described it as “wasted leg syndrome.” Since either one upper or lower limb is affected, Gourie-Devi et al. (1984a, 1986) suggested the eponym “monomelic amyotrophy” (MMA) as a more appropriate term. The authors further suggested that upper limb MMA may be called “brachial mono- melic amyotrophy” to differentiate it from MMA of a lower limb, which may now be called “crural monomelic amyotrophy” (Gourie-Devi and Nalini, 2003). Focal amyotrophy has been described under a variety of descriptive names, which refer to the limb involved, the site of muscles affected and the benign and non-progressive course of the disease (Table 11.1). 11.1.1. Monomelic amyotrophy of upper limb More than 300 cases have been reported from Japan (Hirayama et al., 1963; Hashimoto et al., 1976; Sobue et al., 1978; Hirayama, 2000a). The atrophy was distal and segmental, confined to one upper limb, but electromyographic abnormalities were noted in some patients in the non-atrophic upper limb. From India also more than 200 cases (including a personal series of 89 cases) have been reported of single upper limb atrophy, a large proportion of them with distal muscle involve- ment and a few with proximal muscle involvement (Singh et al., 1980; Gourie-Devi et al., 1984a,b, 1987a; Virmani and Mohan, 1985; Misra and Kalita, 1995; Pradhan and Gupta, 1997; Saha et al., 1997; Khandelwal et al., 2004; Misra et al., 2005). Reports from many other countries including Sri Lanka (Peiris et al., 1989), Korea (Kim et al., 1994), Hong Kong (Chan et al., 1991), Taiwan (Kao et al., 1993a) and Malaysia (Tan, 1985) reaffirm the frequency of MMA in Asia. Initially there were few reports from Western countries, mostly isolated cases or a small number of patients, but with increasing awareness more publications have appeared in the literature (Pilgaard, 1968; Compernolle, 1973; Engel, 1977; Adornato et al., 1978; De Visser et al., 1988). Large series of cases, notably from France and Brazil, have been published (Serratrice et al., 1987; De Freitas and Nascimento, 2000). Hirayama et al. (1963) referred to 10 cases reported by Marie and Foix in 1912, of isolated non-progressive atrophy of small muscles of hand, older age at onset of the disease in the fifth to eighth decades in eight cases and second decade in two cases. The autopsy findings in four of these patients are discussed later (§ 11.12). 11.1.2. Monomelic amyotrophy of lower limb Monomelic amyotrophy of a lower limb is less frequent than MMA of an upper limb. More than 130 cases (including a personal series of 36 cases) have been *Correspondence to: M. Gourie-Devi, Flat 9, Doctors Apartments, Vasundhara Enclave, New Delhi – 110096, India. E-mail: gouriedevi@yahoo.co.in, mgouriedevi@gmail.com, Tel: +91-11-22618573, Fax: +91-11-22599227. Ch11-N51894 9/8/06 10:39 AM Page 207 reported from India (Prabhakar et al., 1981; Gourie- Devi et al., 1984a,b, 1987a; Virmani and Mohan, 1985; Chopra et al., 1987; Saha et al., 1997) and more than 40 cases from Western countries (Riggs et al., 1984; Serratrice et al., 1987; Uncini et al., 1992; De Freitas and Nascimento, 2000; Felice et al., 2003). It is note- worthy that, although numerous cases of MMA of an upper limb are described from Japan, there is only one isolated report of two cases of MMA of a lower limb (Hamano et al., 1999). 11.2. Prevalence and geographic distribution Monomelic amyotrophy constituted 8–29% of all motor neuron diseases in different series reported from India (Gourie-Devi et al., 1984a, 1987a; Saha et al., 1997). The estimated prevalence rate of MMA was 0.9, of upper limb 0.5 and lower limb 0.4 per 100,000 popula- tion (Gourie-Devi et al., 1984a; Gourie-Devi, 2004), based on the ratio of cases of monomelic amyotrophy to amyotrophic lateral sclerosis, as suggested by Kurtzke (1962), the prevalence rate of ALS having been determined to be 4 per 100,000 population (Gourie- Devi et al., 1984a, 1995). The geographic distribution of MMA of upper and lower limb in Asia and other countries is shown in Tables 11.2 and 11.3. 11.3. Classification Monomelic amyotrophy can be classified based on the limb involved and the site of muscles affected: Type 1. Monomelic amyotrophy of upper limb. Distal: Hand and forearm muscles. Proximal: Shoulder girdle and arm muscles. Global: Entire limb. Type 2. Monomelic amyotrophy of lower limb. Distal: Leg and foot muscles. Proximal: Pelvic girdle and thigh muscles. Global: Entire limb. In the majority of cases in both type 1 and type 2, the atrophy is confined to a single limb with electromyo- graphic abnormalities in the contralateral limb in some patients. In type 1, spread to the contralateral limb with atrophy and weakness may occur in 10 to 30%, but significant asymmetry is a distinctive fea- ture, the initially involved limb being more severely affected (Gourie-Devi et al., 1984a; Sobue et al., 1978). In contrast, in type 2, atrophy is usually restricted to a single lower limb (Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; Serratrice et al., 1987) with rare instances of spread to the opposite limb (Kim et al., 1994; Felice et al., 2003). 208 M. GOURIE-DEVI Table 11.1 Eponyms used for single limb atrophy A. Upper and lower limb Monomelic amyotrophy (Gourie-Devi et al., 1984a). Benign focal amyotrophy (Adornato et al., 1978; Riggs et al., 1984). Monomelic spinal muscular atrophy (De Visser et al., 1988). Spinal monomelic amyotrophy (Serratrice, 1991). Benign monomelic amyotrophy (De Freitas and Nascimento, 2000). B. Upper limb Juvenile muscular atrophy of unilateral upper extremity (Hirayama et al., 1959). Juvenile non progressive muscular atrophy localized to hand and forearm (Hashimoto et al., 1976). Juvenile type of distal and segmental muscular atrophy of upper extremities (Sobue et al., 1978). Juvenile muscular atrophy localized to arms (Singh et al., 1980). Juvenile lower cervical spinal muscular atrophy (Kao et al., 1993a). Juvenile amyotrophy of distal upper extremity (Biondi et al., 1989). Non-familial spinal segmental muscular atrophy in juvenile and young subjects (Virmani and Mohan, 1985). Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama’s disease) (Hirayama, 1991). Juvenile asymmetric segmental spinal muscular atrophy (Pradhan and Gupta, 1997). Brachial monomelic amyotrophy (Gourie-Devi and Nalini, 2003). C. Lower limb Wasted leg syndrome (Prabhakar et al., 1981). Benign monomelic amyotrophy of lower limb (Uncini et al., 1992). Benign calf amyotrophy (Felice et al., 2003). Crual monomelic amyotrophy (Gourie-Devi, 2004). Ch11-N51894 9/8/06 10:39 AM Page 208 11.4. Clinical features The age of onset in the majority (90%) varies from 15 to 35 years with a median age of 20 years in MMA of upper limb and slightly older in MMA of lower limb with a median age of 25 years (Hirayama et al., 1963; Sobue et al., 1978; Gourie-Devi et al., 1984a). In excep- tional cases the age at onset can be as early as 2 years and as late as 84 years, the older age at onset being more often noted in MMA of lower limb (Sobue et al., 1978; Serratrice et al., 1987; Felice et al., 2003). However, because the condition is so insidious in onset it can be difficult to determine the age at onset. There is remark- able gender preference, with men outnumbering women with a ratio varying from 3:1 to 20:1, with more men affected in MMA of lower limb compared to MMA of upper limb (Hirayama et al., 1963; Sobue et al., 1978; Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985). The duration of illness at first consultation may vary from a few months to as long as 15 years, with a mean duration of 2.5 to 4.5 years (Hirayama et al., 1963; Prabhakar et al., 1981; Gourie- Devi et al., 1984a; De Freitas and Nascimento, 2000). 11.4.1. Clinical features of MMA of upper limb In monomelic amyotrophy of upper limb, the common initial symptoms are weakness and atrophy in the major- ity, followed by tremulousnesss of fingers. Coarse, intermittent nonrhythmic tremors of fingers present at rest, accentuated by outstretching of hands and on MONOMELIC AMYOTROPHY OF UPPER OR LOWER LIMBS 209 Table 11.2 Geographic distribution of monomelic amyotrophy of upper limb A. Countries in Asia India: Singh et al., 1978; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; Misra and Kalita, 1995; Pradhan and Gupta, 1997; Saha et al., 1997; Nalini et al., 2004; Khandelwal et al., 2004. Hong Kong: Chan et al., 1991. Israel: Neufeld et al., 1991. Japan: Hirayama et al., 1963; Hashimoto et al., 1976; Sobue et al., 1978; Mukai et al., 1985; Iwasaki et al., 1987; Kikuchi et al., 1987; Konno et al., 1997; Kohno et al., 1998. Korea: Kim et al., 1994. Malaysia: Tan, 1985. Sri Lanka: Peiris et al., 1989. Taiwan: Kao et al., 1993a. Turkey: Gucuyener et al., 1991. B. Countries outside Asia Australia: Kiernan et al., 1999. Belgium: Robberecht el al., 1997. Brazil: De Freitas and Nascimento, 2000. Canada: Oryema et al., 1990. Denmark: Pilgaard, 1968. France: Serratrice et al., 1987; Chaine et al., 1988; Biondi et al., 1989. Germany: Schlegal et al., 1987; Schroder et al., 1999. Italy: Barontini et al., 1991; Di Guglielmo et al., 1996; Polo et al., 2003. Netherlands: Compernolle, 1973; Thijsse and Spaans, 1983; De Visser et al., 1988. Poland: Drozdowski et al., 1998. Switzerland: Kaeser et al., 1983. USA: Engel, 1977; Adornato et al., 1978; Metcalf et al., 1987; Tandan et al., 1990; Liu and Specht, 1993; Donofrio, 1994; Rowin et al., 2001. Table 11.3 Geographic distribution of monomelic amyotrophy of lower limb A. Countries in Asia India: Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; Saha et al., 1997. Japan: Hamano et al., 1999. Korea: Kim et al., 1994. B. Countries outside Asia Austria: Willeit et al., 2001. Brazil: De Freitas and Nascimento, 2000. France: Nedelec et al., 1987; Serratrice et al., 1987. Germany: Munchau and Rosenkranz, 2000. Italy: Uncini et al., 1992; Di Muzio et al., 1994; Di Guglielmo et al., 1996. Netherlands: De Visser et al., 1988. Spain: Martinez et al., 1990. USA: Riggs et al., 1984; Felice et al., 2003. Ch11-N51894 9/8/06 10:39 AM Page 209 voluntary action is present in 60 to 80% of patients (Hirayama et al., 1963; Gourie-Devi et al., 1984a). This feature has been observed in spinal muscular atrophy and the descriptive term minipolymyoclonus has been coined (Spiro, 1970). Minipolymyoclonus needs to be distinguished from tremors, which are generally rhyth- mic, and from fasciculations. Discharges by motor neu- rons innervating large territory of muscle are implicated in the causal mechanisms of these tremor-like move- ments, but probably not specific, and may be seen in hand weakness from most neuromuscular disorders. Fasciculations are commonly observed in atrophic muscles and also in the unaffected muscles in a few patients. Hirayama (1972) described “cold paresis,” an interesting phenomenon of aggravation of weakness on exposure to cold. Some of them also complain of stiff- ness of hands on dipping the hands in cold water, how- ever there was no clinical or electromyographic evidence of myotonia (Gourie-Devi et al., 1984a). In MMA of upper limb the distal muscles of hand and forearm are affected in more than 50% of patients, prox- imal muscles of shoulder and upper arm in 5–10% and diffuse involvement in 40% with the distal muscles more severely affected than proximal muscles. Small muscles of the hand, flexors and extensors of the wrist, chiefly C7-T1 spinal segments, are the most severely affected muscles (Figs. 11.1–11.3). Relative sparing of brachiora- dialis muscle among surrounding atrophic muscles (Fig. 11.2) is a characteristic feature of this disease (Hirayama et al., 1963). In the diffuse form with involve- ment of an entire upper limb, the additional muscles atro- phied are biceps, triceps, deltoid and scapular muscles (Compernolle, 1973; Thijsse, 1983; Gourie-Devi et al., 1984a). Unilateral atrophy of scapulohumeral muscles in C5–C6 myotomes (Fig. 11.4) was described by Kaeser (1983) from Switzerland and similar cases were observed by others (Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; Amir et al. 1987; De Visser et al., 1988; Kao et al., 1993a). The pattern of muscles affected in our series of 89 patients (Gourie-Devi and Nalini, unpublished observations) is shown in Figure 11.5. 11.4.2. Clinical features of MMA of lower limb In MMA of lower limb, atrophy of the limb was noted by the patient because of pain on walking, and in nearly a third of the patients it was incidentally observed by a family member, friend or physician during consultation for unrelated illness (Prabhakar et al., 1981; Gourie-Devi et al., 1984a). Under these circumstances the precise age at onset and duration of illness may not be accurate. Muscle cramps and fasciculations have been observed in 20 to 30% of patients. Unilateral pes cavus may be a presenting feature (De Freitas and Nascimento, 2000). Unlike as in postpoliomyelitis progressive muscular atrophy there is no shortening of limb. 210 M. GOURIE-DEVI Fig. 11.1. Mild atrophy of flexors of forearm of right upper limb best seen in semiprone position. Ch11-N51894 9/8/06 10:39 AM Page 210 MONOMELIC AMYOTROPHY OF UPPER OR LOWER LIMBS 211 Fig. 11.2. Atrophy of flexor and extensor muscles of right forearm with sparing of brachioradialis muscle and mild wasting of hand muscles. Fig. 11.3. Severe atrophy of thenar, hypothenar and interossei, particularly first dorsal interosseous muscle of right hand. Fig. 11.4. Severe wasting of left shoulder and upper arm muscles with normal forearm muscles. Ch11-N51894 9/8/06 10:39 AM Page 211 In the distal form, which accounts for 20% of cases, with predominant calf muscle atrophy, inability to stand on tiptoe is a presenting feature (Felice et al., 2003). Anterior and posterior crural muscles are most com- monly affected (Fig. 11.6), while intrinsic foot muscles are infrequently involved (Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; De Visser et al., 1988; Uncini et al., 1992; Hamano et al., 1999; De Freitas and Nascimento, 2000; Felice et al., 2003). In the proximal type, isolated atrophy of quadri- ceps (Fig. 11.7) may occur (Prabhakar et al., 1981; Gourie-Devi et al., 1984a) or may be involved along with hamstring muscles (Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Riggs et al., 1984; Virmani and Mohan, 1985). The commonest type is involvement of the entire limb with atrophy of proximal and distal muscles and has been observed in 70% of patients (Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; Hamano et al., 1999). The pattern of muscle involvement in our series of 36 cases (Gourie-Devi and Nalini, unpub- lished data) is shown in Figure 11.8. 11.4.3. Other clinical features The tendon reflexes in the affected limb in both type 1 and 2 are usually absent or sluggish. In some patients they are normal and brisk reflexes are rare, but plantar response is invariably flexor. In the unaffected homolo- gous limb and other limbs, the reflexes were generally normal and infrequently sluggish. Although subjective symptoms of numbness have been reported, no objec- tive sensory deficit has been documented. Excessive sweating and coldness of affected limb is a frequent feature. Cognitive function, cranial nerves, pyramidal, extrapyramidal and cerebellar systems are not involved. There is no evidence of other neurological disorders in the affected subject or their family members. 11.5. Associated factors and antecedent events Febrile illness, vaccination, exposure to toxic sub- stances and electric shock preceding the illness have 212 M. GOURIE-DEVI 31 12 12 43 37 69 19 62 62 81 56 94 69 94 94 94 Scapular Latissmus dorsi Pectoralis Major Deltoid Biceps Brachialis Triceps Brachioradialis Supinator Pronator Wrist Flexors Wrist Extensors Finger Flexors Finger Extensors Thenar Hypothenar Interossei Fig. 11.5. Pattern of muscle atrophy and weakness in 89 patients of monomelic amyotrophy of upper limb (Gourie- Devi and Nalini, unpublished data). Fig. 11.6. Atrophy of calf muscles of right leg. Ch11-N51894 9/8/06 10:39 AM Page 212 not been observed in the majority of patients (Hirayama et al., 1963; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985, Peiris et al., 1989). In rare instances poliomyelitis in childhood has been reported (Gourie-Devi et al., 1984a; Peiris et al., 1989; Gourie- Devi, 1996). Mechanical trauma including injuries or surgery have been recorded preceding the onset of neu- rological symptoms by many months to years and in some of them atrophy occurred in the previously injured limb (Sobue et al., 1978; Gourie-Devi et al., 1993; Paradiso, 1997). In a case control study which examined the risk factors in 21 cases and 63 age and gender matched control subjects, strenuous physical activity was observed to be a significant associated factor (Gourie-Devi et al., 1993). Occupations involv- ing heavy manual exertion and participation in com- petitive sports have also been recorded in patients with MMA (Hashimoto et al., 1976; Prabhakar et al., 1981; Biondi et al., 1989). 11.6. Familial monomelic amyotrophy Familial occurrence of MMA is extremely rare. Gourie- Devi et al. (1984a) did not detect muscle weakness, wasting or sluggish tendon reflexes in 48 siblings and parents of 17 patients. A total of 15 families have been reported so far from countries in Asia, Europe and USA (Table 11.4). Two brothers were affected in each of six families, father and son in four, mother and son in two families, sister and brother, identical twin brothers and two half brothers in one family each. In 13 families the upper limb was involved and in two families lower limb was affected. The age at onset was in the second or MONOMELIC AMYOTROPHY OF UPPER OR LOWER LIMBS 213 27 45 81 45 100 37 36 81 Glutei Adductors Quadriceps Hamstring Anterior Crural Peronell Posterior Crural Foot Muscles Fig. 11.8. Pattern of muscle atrophy and weakness in 36 patients with monomelic amyotrophy of lower limb (Gourie- Devi and Nalini, unpublished data). Fig. 11.7. Atrophy of thigh muscles of right lower limb with preserved calf muscles. Ch11-N51894 9/8/06 10:39 AM Page 213 third decade in 13 families, first decade in one family (Gucuyener et al., 1991) and fifth decade and beyond in one family (Serratrice et al., 1987). There were 25 males and three females with a M:F ratio of 8.3:1. These reports suggest autosomal recessive inheritance in some families and autosomal dominant inheritance with vari- able expression in others (De Visser et al., 1991; Robberecht et al., 1997; Nalini et al., 2004). Occurrence of disease predominantly in males and two half brothers may indicate X-linked recessive inheritance which needs to be further examined (Nedelec et al., 1987; Misra et al., 2005). Only a few genetic studies have been done. In one family in two affected brothers, five exons of superox- ide dismutase 1 (SOD 1) gene were normal and the SOD activity in patients’ RBC was comparable to the values in control subjects (Robberecht et al., 1997). Subsequently, Mezei et al. (1999) describe a family with a D90A SOD1 mutation in which the father of the proband has clinical features typical of lower limb monomelic amyotrophy. DNA analysis revealed him to be heterozygous for D90A mutation. Survival motor neuron gene (SMN) deletion in the region of 5q13 has been demonstrated to be associated with phenotypic expression of spinal muscular atrophy (SMA) (Lefebvre et al., 1995) and for confirmatory diagnosis of SMA, SMN1 and SMN2 gene deletion study is advocated (Scheffer et al., 2001). It has also been shown that dele- tions in SMN gene occur in adult onset SMA (Brahe et al., 1995). Since MMA has been considered as a focal form of SMA, studies have been done to examine the deletion of SMN gene. Recent reports from Italy, USA and India show that MMA of upper and lower limb are not associated with deletions in exons 7 and 8 of the SMN gene (Di Guglielmo et al., 1996; Felice et al., 2003; Misra et al., 2005). Mutation of mitochondr- ial DNA, the 7472 insC in the gene coding the tRNA Ser (UCN), has been reported from Italy in a patient with monomelic amyotrophy and sensorineural hearing loss in the patient, his mother and an elder sister (Fetoni et al., 2004). Association of lower motor neuron involve- ment with mt DNA mutation needs further elucidation. 11.7. Secondary monomelic amyotrophy Monomelic amyotrophy may be secondary to demon- strable causes including irradiation, atopy and human immunodeficiency virus (HIV) infection. Lower motor neuron syndrome may develop months to years after irradiation for malignant disorders encompassing the spinal cord. In most cases paraparesis has been reported but rarely cases with monomelic amyotrophy have been documented (Lamy et al., 1991; Jackson, 1992; Serratrice et al., 1993). The period between radiotherapy and development of MMA ranged from 9 to 17 years. It is possible that radiotherapy damaged a critical number of motor neurons and the compensatory efforts of surviving motor neurons in reinnervation of muscles could not be maintained over many years, leading to focal atrophy (Jackson, 1992). However, radiation necrosis more commonly affects the plexus and proximal nerves. Asthmatic amyotrophy, a polio-like syndrome, is characterized by an asymmetrical lower motor neuron paralysis following an acute episode of asthma (Hopkins, 1974; Batley and Johnson, 1991). Importance of atopy, airways allergy in precipitating ‘circulatory insuffi- ciency’ and its causal linkage to acute myelitis and to the 214 M. GOURIE-DEVI Table 11.4 Familial case of monomelic amyotrophy Author (year) Country Families Affected Limb Igata et al. (1966) Japan 1 Father–son UL Hirayama (1972) Japan 3 Brothers (2) UL Sobue et al. (1978) Japan 1 Father–son UL Hirayama et al. (1987) Japan 1 Brothers (2) UL Schlegel et al. (1987) Germany 1 Father–son UL Serratrice et al. (1987) France 1 Mother–son LL Nedelec et al. (1987) France 1 Brothers (2) LL Tandan et al. (1990) USA 1 Identical twin-brother UL Gucuyener et al. (1991) Turkey 1 Sister–brother UL Misra and Kalita (1995) India 1 Brothers (2) UL Robberecht et al. (1997) Belgium 1 Brothers (2) UL Nalini et al. (2004) India 1 Mother–son UL Misra et al. (2005) India 1 Brothers (2) UL Figure in parenthesis indicates number of affected members. Ch11-N51894 9/8/06 10:39 AM Page 214 chronic disorder of monomelic amyotrophy has been suggested (Kira et al., 1998; Horiuichi et al., 2000; Kira and Ochi, 2001). In HIV infection, several neurological disorders are described, but motor neuron disease has been very rarely reported (Huang et al., 1993; Moulignier et al., 2001). A significant proportion of these patients were young, the initial presentation was monomelic amyotrophy with subacute progression to other limbs and involvement of corticospinal tracts. The striking response to antiretro- viral therapy convincingly establishes the etiological relationship between HIV and motor neuron disease, in these select patients (Jubelt and Berger, 2001; Moulignier et al., 2001). 11.8. Investigations 11.8.1. Laboratory tests Routine blood and cerebrospinal fluid analysis is usu- ally normal, but a mild rise of CSF protein has been seen in a few patients (Hirayama et al., 1963; Gourie-Devi et al., 1984a). A slight increase in serum creatine kinase level, just above the normal range, has been reported in occasional patients (Gourie-Devi et al., 1984a). Antibodies to viruses such as polio, Coxackie B, Echo, influenza A and B, adeno and herpes simplex were not detected in CSF (Sobue et al., 1978; Virmani and Mohan, 1985). Lower serum neutralizing antibody titers for poliovirus were found in patients compared to con- trols suggesting that patients with MMA may be immunologically unresponsive to a neutralizing epitope of poliovirus (Kao et al., 1993b). Intrathecal immuno- globulin synthesis was not detected and ganglioside antibodies, particularly anti-GM 1 antibodies, were not detected (Willeit et al., 2001). 11.8.2. Muscle biopsy Variable findings of normal to small groups of angu- lated muscle fibers, group atrophy, nuclear clumping, fiber type grouping to end stage disease with diffuse fatty infiltration and prominent increase in connective tissue, all features suggestive of neurogenic atrophy in the affected limb, have been noted in various studies (Hirayama et al., 1963; Prabhakar et al., 1981; Gourie- Devi et al., 1984a; Kao and Tsai, 1994; Kim et al., 1994). Necrotic fibers with central nuclei, basophilic fibers with large vesicular nuclei indicating secondary myopathic changes, were observed in a few patients (Prabhakar et al., 1981; Gourie-Devi et al., 1984a). Subclinical diffuse involvement of anterior horn cells was supported by evidence of mild muscle fiber type grouping in the unaffected limb (Uncini et al., 1992). Sural nerve biopsy did not show any abnormality (Gourie-Devi et al., 1984a; Kim et al., 1994). 11.8.3. Electrophysiology 11.8.3.1. Electromyography Needle electromyography shows fibrillations or positive sharp waves, long duration, large amplitude polyphasic potentials with poor recruitment indicating both active denervation and chronic reinnervation, respectively, in the atrophic muscles of the affected limb in MMA of upper or lower limbs (Hirayama et al., 1963; Sobue et al., 1978; Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Serratrice et al., 1987; Peiris et al., 1989; Kao et al., 1993a; Kim et al., 1994; Khandelwal et al., 2004; Misra et al., 2005). Active denervation, a consistent fea- ture in the majority of cases, irrespective of the duration of illness ranging from few months to 5 or more years, was not seen in the patients who had attained a station- ary course after an initial phase of progression (Kao et al., 1993c; Misra and Kalita, 1995; Gourie-Devi and Nalini, 2003). Rarely fibrillations or positive sharp waves have been observed in a clinically stationary phase of many years, suggesting a subclinical progres- sion (Kao et al., 1993c). In the clinically unaffected muscles of the involved limb chronic reinnervative changes have been reported in 25 to 50% of patients with amyotrophy of upper limb (Gourie-Devi et al., 1984a; De Visser et al., 1988; Hirayama, 2000a), however no abnormalities have been reported by other authors (Virmani and Mohan, 1985; Kim et al., 1994; Misra et al., 2005). It is important to note that the relatively well preserved brachioradialis muscle usually does not show any EMG abnormalities (Hirayama et al., 1963; Gourie-Devi et al., 1984a; Misra and Kalita, 1995), with few exceptions (Sobue et al., 1978). In the contralateral unaffected upper limb, the homologous muscles show denervation and chronic rein- nervation in 7–88% of patients (Hirayama et al., 1963; Hashimoto et al., 1976; Sobue et al., 1978; Singh et al., 1980; Gourie-Devi et al., 1984a; De Visser et al., 1988; Gourie-Devi and Nalini, 2003; Khandelwal et al., 2004; Misra et al., 2005) but were found to be normal by some authors (Virmani and Mohan, 1985). In the lower limbs which are clinically never affected, EMG abnormalities have not been demonstrated in the vast majority of patients (Hirayama et al., 1963; Hashimoto et al., 1976; Singh et al., 1980; Sobue et al., 1978; Gourie-Devi et al., 1984a; Willeit et al., 2001; Gourie-Devi and Nalini, 2003) with rare exceptions of mild chronic denervation (De Freitas and Nascimento, 2000). In MMA of lower limb, denervation and chronic reinnervation have also been noted in the clinically unaffected muscles of the atrophic limb but very rarely in the contralateral lower limb (Prabhakar et al., 1981; Gourie-Devi et al., 1984a; Riggs et al., 1984; Virmani and Mohan, 1985; Uncini et al., 1992; Munchau and Rosenkranz, 2000; Felice et al., 2003). The upper limbs in this group do not show any abnormalities. MONOMELIC AMYOTROPHY OF UPPER OR LOWER LIMBS 215 Ch11-N51894 9/8/06 10:39 AM Page 215 Electromyography did not reveal any evidence of myotonic discharges, particularly in the context of appearance of stiffness of hands on exposure to cold (Gourie-Devi et al., 1984a). Aggravation of weakness of fingers induced by exposure to cold has been attrib- uted to impairment of muscle membrane conduction since high frequency repetitive nerve stimulation showed waning of amplitude of compound muscle action potentials (Kijima et al., 2002). Only in a single case of MMA of upper limb were myokymic discharges observed (De Visser et al., 1988). Lower cervical paraspinal muscles (C8-T1) involve- ment on electromyography was not observed in MMA of upper limb, although active denervation and chronic reinnervation could be demonstrated in the muscles of C7-T1 myotomes in the affected upper limbs, independ- ent of the clinical stage of the disease or the duration of illness (Kao et al., 1993c). In contrast, paraspinal muscle involvement, an early and consistent sign demonstrable by EMG in amyotrophic lateral sclerosis (Kuncl et al., 1988), can help in differentiating ALS from monomelic amyotrophy, particularly when the initial feature is single limb involvement (Kao et al., 1993c). Single fiber EMG done in a few patients showed increased fiber density and jitter with occasional block- ing in the affected limb, indicating unstable neuromus- cular transmission due to new regeneration (Thijsse and Spaans, 1983). During the stage of stabilization of the disease, there is further increase of fiber density, but jitter decreases suggesting maturation of reinnervation (Hirayama, 2000a). 11.8.3.2. Nerve conduction Motor conduction studies are usually normal in patients with mild to moderate atrophy of muscles (Hirayama et al., 1963; Sobue et al., 1978; Singh et al., 1980; Gourie-Devi et al., 1984a; Virmani and Mohan, 1985; De Visser et al., 1988; Peiris et al., 1989). Slight slow- ing of motor conduction velocity may be observed con- sistent with loss of fast conducting axons and the compound muscle action potential amplitude is reduced (Kim et al., 1994) and occasionally motor distal latency may be prolonged (Tan, 1985). Conduction block has not been demonstrated in amyotrophy of upper or lower limb (Kim et al., 1994; Misra and Kalita, 1995; Gourie- Devi and Nalini, 2001; Willeit et al., 2001; Khandelwal et al., 2004). Sensory conduction studies are normal in all patients. F-wave latency and H-reflex are within normal limits (Uncini et al., 1992; Kao et al., 1993c; Misra and Kalita, 1995; Willeit et al., 2001) with few exceptions of slight increase in latency and low persistence of F-wave (Kuwabara et al., 1999). 11.8.3.3. Evoked potentials Somatosensory evoked potentials (SEP) from upper and lower limbs are normal in amplitude and latency (Kao et al., 1993c; Pradhan and Gupta, 1997; Willeit et al., 2001). Conflicting results show decrease of amplitude of Erb’s point potentials and N13 spinal responses but with normal latencies and normal N20 potential (Polo et al., 2003). There was no correlation of these abnor- malities with the clinical features. However, SEPS were found to be normal following tibial nerve stimulation. 11.8.3.4. Central motor conduction Central motor conduction time (CMCT) determined by electrical stimulation of cortex or by transcranial mag- netic stimulation was normal in all patients, providing evidence that in MMA upper motor neuron is not involved (Misra and Kalita, 1995; Khandelwal et al., 2004). Contrary to these findings, slight but significant prolongation of CMCT has been observed in some patients (Polo et al., 2003). Cortical threshold intensity (TI) which reflects a balance of cortical and spinal excitability was also found to be normal (Khandelwal et al., 2004). In motor neuron disease the CMCT and TI have been found to be abnormal confirming upper motor neuron involvement (Triggs et al., 1999), while in MMA there is no evidence of pyramidal tract dys- function. The absence of upper motor neuron involve- ment in MMA has also been substantiated by normal H/M ratio, vibratory inhibition and reciprocal inhibi- tion of soleus H reflex (Misra and Kalita, 1995). 11.8.3.5. Dynamic electrophysiology Dynamic electrophysiological studies showed increased latency and decreased amplitude of motor evoked poten- tials after transcranial magnetic stimulation, decrease in F-wave persistence and decrease of amplitude of N13 somatosensory evoked potential during neck flexion (Shizukawa et al., 1994; Kuwabara et al., 1999; Restuccia et al., 2003). 11.8.4. Autonomic function tests and sympathetic skin response Increased sweating of hands and cyanosis of fingers have been observed in nearly 50% of patients with MMA of upper limb (Hirayama et al., 1963; Gourie- Devi et al., 1984a). Decreased skin temperature in distal portion of upper limb, plethysmographic abnor- malities indicative of vasomotor dysfunction and con- firmation of hyperhidrosis by sweat tests have been documented (Hirayama, 1991). A recent study of sympathetic skin response (SSR) in MMA showed that SSR latency in the affected upper 216 M. GOURIE-DEVI Ch11-N51894 9/8/06 10:39 AM Page 216 [...]... stimulation of the distal part of the segment with motor CB of at least 1 mV 2 Probable motor CB: CMAP amplitude reduction on proximal versus distal stimulation of at least 30% over a long segment of an arm nerve CMAP amplitude on stimulation of the distal part of the segment with motor CB of at least 1 mV 3 Slowing of conduction compatible with demyelination: MCV < 75% of the lower limit of normal; DML or shortest... Differential diagnosis of spinal muscular atrophies and other disorders of motor neurons with infantile or juvenile onset In: de Jong JMBV (Ed.) Diseases of the Motor System, Handbook of Clinical Neurology, Vol 15 (59) Elsevier, Amsterdam, pp 367–382 Di Guglielmo G, Brahe C, Di Muzio A, Uncini A (1996) Benign monomelic amyotrophies of upper and lower limb are not associated to deletions of survival motor... Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama’s disease) In: de Jong JMBV (Ed.) Diseases of the Motor System Handbook of Clinical Neurology, Vol.1 5 (59) Elsevier, Amsterdam, pp 107–120 Hirayama K (2000a) Juvenile muscular atrophy of distal upper extremity (Hirayama disease) Intern Med 39: 283–290 Hirayama K (2000b) Juvenile muscular atrophy of distal upper extremity (Hirayama... Italy, of a young man from South India with MMA, after a stationary phase of 11 years, developed fresh neurological features, suggestive of Madras MND, is of interest (Massa et al., 1998) The criteria for “late progression of poliomyelitis” suggested by Mulder et al (1972) are (a) a credible history of poliomyelitis, (b) partial recovery of function, (c) a minimum 10-year period of stabilization of this... MMA of lower limb, except for mild difficulty in walking and running, there was no significant disability (GourieDevi et al., 1984a) 11.12 Pathology The earliest pathological description of spinal cord in elderly patients above 70 years of age with clinical features resembling MMA is by Marie and Foix (1912) 222 M GOURIE-DEVI Softening of anterior horn of spinal cord corresponding to the side of the... studies and absence of conduction block provide confirmation of localization of lesion to anterior horn cells Imaging of spinal cord to exclude mass lesions, syringomyelia and vascular lesions is mandatory An algorithm (Fig 11.12) provides a practical approach to diagnosis of monomelic amyotrophy 11.10 Differential diagnosis Before considering the diagnosis of MMA of upper limb, a number of disorders which... extension to C5 to T1 Atrophy of spinal cord at C7–C8 levels, thinning of C7 to T1 anterior roots, marked shrinkage of anterior horns, decrease of large and small nerve cells, chromatolysis, lipofuscin accumulation, occasional basophilic inclusions in the remaining neurons and mild astrogliosis were the salient observations There was no evidence of vascular or inflammatory changes Loss of myelinated fibers... multiplex can manifest as focal atrophy of one limb Electromyography and nerve conduction studies provide confirmation of diagnosis Special mention needs to be made of multifocal motor neuropathy (MMN) with the characteristic features of pattern of muscle involvement in peripheral nerve distribution, association with GM1 antibodies in 50–80% of patients and conduction block of one or more nerves in proximal... Nalini (2003), in a large series of patients with long term follow-up of clinical status and EMG, observed that there was clinical arrest of the disease within 5 years in 75% to 80% In 5–7%, the disease had progressed up to 8 years, followed by a stationary phase (Gourie-Devi and Nalini, 2003) Slight atrophy and tremors of the contralateral upper limb was present in 16% (seven of 44 patients) at 221 presentation... (2002) Mimic syndromes in sporadic cases of progressive spinal muscular atrophy Neurology 58: 1593–1596 Willeit J, Kiechl S, Kiechl-Kohlendorfer U, Golaszewski S, Peer S, Poewe W (2001) Juvenile asymmetric segmental spinal muscular atrophy (Hirayama’s disease) Three cases without evidence of ‘flexion myelopathy’ Acta Neurol Scand 104: 320–322 Handbook of Clinical Neurology, Vol 82 (3rd series) Motor Neuron . Diseases of the Motor System. Handbook of Clinical Neurology, Vol. 15 (59). Elsevier, Amsterdam, pp. 107– 120 . Hirayama K (20 00a). Juvenile muscular atrophy of. nosological study of 25 cases of chronic monomelic amyotrophy. Rev Neurol 143: 20 1 21 0. 22 6 M. GOURIE-DEVI Ch11-N51894 9/8/06 10:39 AM Page 22 6