Progressive muscle weakness

Limb-girdle (proximal) weakness

Chronic

Drug/toxin-induced myopathy: The following drugs may give rise to myopathy chlorquine, clofibrate, colchicine, AZT, vincristine, alcohol, corticosteroids and statins. Toxic oil syndrome due to adulterated rapeseed oil also cause inflammatory myopathy in addition to inflammatory polyneuropathy.

Acid maltase deficiency type II (AMD): AMD is an autosomal recessive disorder caused by the absence of the lysosomal enzyme acid a-glucosidase. The adult variant manifests itself mostly after the 2^nd decade of life. Three forms can be distinguished: 1) only limb-girdle (weakness of pelvic girdle, predominantly in glutei and thigh adductors) involvement ; 2) limb-girdle involvement (predominantly pelvic-girdle weakness) with additional early progressive respiratory insufficiency out of proportion to limb weakness; and 3) respiratory muscles weakness without any other severe muscle involvement. The latter may present as chronic progressive fatigue, hypersomnolence, sleep apnoea and exertional dyspnea with restrictive respiratory insufficiency and signs of cor pulmonale (vital capacity less than 60%). Respiratory insufficiency is the most frequent cause of mortality from AMD. Occasionally, the clinical spectrum may extend to include a scapuloperoneal weakness with scapular winging, asymmetric muscle weakness, tongue involvement, intracranial aneurysm or arteriopathy in late-onset forms and, rarely, cardiomyopathy. Consistent supportive abnormalities include a modest elevation in serum aminotransferases and to lesser extent of CK, the reduced activity of lymphocytic acid a-glucosidase, a reduction in the forced vital capacity, and abnormal spontaneous activity in resting muscles during needle EMG. MRI may reveal adipose tissue infiltration in proximal muscles of the legs. The diagnosis is readily confirmed by muscle biopsy. Patients are generally compound heterozygotes for various mutations in the GAA gene (muscle, fibroblast, lymphocytes) located on chromosome 17q. The most common mutant allele is a -13T to G transversion in intron 1 (chromosome 17q23). Tracheostomy has to be considered in case of aspiration. Enzyme replacement therapy with recombinant a-glucosidase is now available. Differential diagnosis include muscular dystrophies (LGMD, Becker MD, scapuloperoneal MD), genetic metabolic diseases (glycogen storage diseases [debrancher deficiency, branching enzyme deficiency, myophosphorylase deficiency, phosphofructokinase deficiency) and mitochondrial disorders, and polymyositis.

Corticosteroid myopathy: Prolonged use of steroids results in proximal limb and girdle weakness, with legs weaker than arms. Serum CK levels are usually normal. The EMG is either normal or mildly myopathic with no fibrillations. Biopsy is not typical. There is no correlation between the total dose of corticosteroid and the severity of muscle weakness, but generally patients who develop this type of myopathy have been receiving corticosteroids for several months and years and in high doses. Discontinuation or dose reduction may improve the symptoms and lead to recovery over about 2 months.

Endocrine myopathies: Hyperthyroidism, hypothyroidism, Cushing disease, Addison disease, hyperparathyroidism all cause mild proximal myopathy. Serum CK levels are usually normal, except a mild elevation in hypothyroidism. EMG is often normal or nonspecific and muscle biopsy shows only mild nonspecific myopathic changes.

Tryptophan-induced eosinophilia myalgia syndrome: This results in painful fasciitis, sclerodermatous skin changes, myalgia, arthralgia, rash, alopecia, edema cough or fever. The proximal muscles are affected and 2/3 of patients have a demyelinating neuropathy.

Myasthenia gravis (MG): The prevalence of MG in the general population is around 0.1‰. MG is a heterogeneous autoimmune disorder with regard to age of onset of disease, serum titers of anti-AchR antibodies, and severity of clinical symptoms. The disease predominates in women (affected twice as much as men) and most commonly peaks in the 2^nd - 3^rd decades, while the peak age in man occurs at later age 5^th - 6^th decade. In 5% of patients, MG is associated with other autoimmune diseases such as autoimmune thyroiditis, RA, SLE and pernicious anemia. In a large majority of patients (80‑90%) suffering from MG, these autoantibodies are found in the serum. MG is a monophasic illness, which begins relatively acutely in most patients (often following surgery, trauma, infection or pregnancy). The hallmark of MG is fluctuating weakness and muscle fatigability, particularly of ocular muscles (initially 40% and eventually 85%). Bulbar symptoms (dysphagia or dysarthria), leg weakness and generalized weakness with fatigue and muscle pain (low back pain) are found each in about 10% of patients. The pure ocular form of MG is observed in 15‑20% of patients. About 10-15% of MG patients have a thymoma. Two tests are of immediate diagnostic help in MG: the most direct confirmatory study is the edrophonium (Tensilon) test (sensitivity 80‑90%) and the repetitive supramaximal nerve stimulation (3 Hz) of the median nerve, which reveals a decremental response of the CMAP amplitude: in about 50% of MG patients a decrement (>10% decrease in CMAP amplitude of the 5^th potential vs. 1^st potential) to repetitive nerve stimulation is found. However in patients with pure ocular or mild generalized weakness the test is less likely to be positive. With regards to the edrophonium test, one or preferably two reliable endpoints (ptosis, dysconjugate gaze,...) must be taken as reference. Anti-AchR antibodies are found in 70-85% of all patients with generalized MG and around 50% of patients with the ocular form. The levels of the anti-AchR antibodies do not predict the severity or clinical course of the patient. Anti-AchR antibodies are almost invariable found in patients with both MG and associated thymoma. Patients with thymoma-associated MG, late age at disease onset (mean 65 years) and with intermediate titers of anti-AchR antibodies have high prevalence (55%) of anti-titin antibodies and anti-muscle-specific tyrosine kinase. Ryanodine receptor and anti-titin antibodies present in 70% and 95% of thymoma and 14% and 58% of late onset MG, respectively. The long‑term natural course of MG is highly variable. Generalization usually develops within the first year of the disease while spontaneous long-lasting remission occurs in 10‑15% of cases, usually in the first two years of the disease. Thymectomy is generally recommended for thymoma, moderate to severe MG inadequately controlled with pyridostigmine, and those patients <55 years. An estimated 75% of MG patients will benefit from thymectomy, and the intervention appears to be most efficient the first two years of the disease. Thymectomy is classically a long-term therapy and its effect may not be apparent until after 1 year. Thymectomy appears to increase the likelihood of long-term remission and possibly reduces the long-term exposure to immunosuppressive drugs. 80% of patients will respond favorable response to steroids. Corticosteroids (1mg/kg/d in 3 divided doses e.g. 20 mg tid or 120 mg alternate days) are used in patients with moderate to severe disabling symptoms that are refractory to pyridostigmine and require hospitalization due to risk of early exacerbation (first few days of therapy and lasting about 3-4 days or 2 weeks). However transient initial severe exacerbation (10% of patients) requiring mechanical ventilation or tube feeding may occur after 1 - 3 weeks. Maximum dose should be maintained until complete remission is accomplished (about 3 months), than tapering (5-10%/month) can begin. Steroid sparing can be envisaged with azathioprine (initially 1 mg/kg/day to a maintenance dose of 2-3 mg/kg/day). Short-term effects (1-2 months) are achieved with plasmapheresis and IVIg. Improvement starts within a few days after the onset of the treatment and is meaningful after 14 days, persisting at 1 month. Mostly patients with severe disease benefit from IVIg. In patients with Osserman classification grade > 2 plasmapheresis (5 sessions on alternate day basis over 1 week, each session removing 2.5-4 L of plasma to be replaced by 5% albumin in saline (ml/ml) including 1 L of fresh frozen plasma pre-thymectomy)) is indicated pre-thymectomy. Parameters such as fibrinogen, coagulation factors, calcemia should be monitored. Anticholinergic therapy should be continued tilt the morning of the intervention (1 mg iv or im neostigmine = 30 mg pyridostigmine po, e.g 1 mg iv q4h). Prednisolone 20 mg w or w/o cyclophosphamide 50 mg can be added if required pre-thymectomy. The post-operative dose of pyridostigmine is generally 25-50% of the pre-operative dose.  In acute cases, monitoring should be done by respiratory rate, pulse oximetry, FVC (intubation if FVC<15 ml/kg), arterial blood gases every 2 hours. Cranial neuropathies (diabetes and botulism, mitochondrial disorders, hypothyroidism, myopathies or MND), Wernicke encephalopathy, MFS, ALS, SMA, LEMS and drug-induced MG need to be excluded in the differential diagnosis. Congenital MG should always be considered in patients with seronegative MG, as in those cases there is a high prevalence of autoimmune conditions like thyroid disease, polymyositis, SLE, RA and pernicious anemia.

Debrancher enzyme deficiency type III or Forbes-Cori disease (DED3): The clinical appearance of this autosomal recessive (chromosome 1p21) myopathy is highly variable. In the adult forms (starting in the 3^rd and 4^th decade) we differentiate several phenotypes: (1) muscular symptoms in adult years while the liver symptoms start in childhood, (2) muscle weakness starting in adult years long after liver symptoms in childhood have remitted, (3) only muscular symptoms as adults without any sign or history of liver dysfunction since childhood. Rapid fatigue and aching of muscles is a common presentation, occurring at exertion and beginning at an early age. The myopathy can also have different forms: (1) adult onset distal myopathy (distal leg weakness and intrinsic hand muscles); (2) subacute myopathy of the respiratory muscles; (3) severe generalised myopathy; and (4) minimal variant myopathy. Exercise intolerance is uncommon. Rarely, a mild polyneuropathy may be observed. The clinical course is complicated by advanced liver dysfunction and by severe cardiomyopathy. All patients have raised CK concentrations (up to 800 U/l), myogenic and neurogenic (denervation) features with pseudomytonic discharges on EMG, and markedly decreased debrancher enzyme activities in muscle or liver biopsy specimens. Leucocyte glycogen debrancher enzyme assay provides the diagnosis.

Polyglucosan body myopathy: Late-onset progressive weakness (50s and 60s) affecting proximal limb muscles, increasing distal paresis and only slight weakness of the proximal limb-girdle musculature.

Proximal myotonic myopathy (PROMM) or myotonic dystrophy type 2 (DM2): The age of onset is in the 2^nd or 4^th decade of life (age range 13 – 67 years, median 48 years). This autosomal dominant multisystem disorder is characterized by a characteristic pattern of muscle weakness involving proximal leg weakness (hip flexor and extensors), neck flexors, elbow extensors, thumb and deep finger flexors, and without atrophy (as opposed to distal involvement in DM1), clinical myotonia and myalgias, and cataract (before the age of 40 years). Fluctuating or episodic muscle pain is common in patients > 50 years. Further typical features are cardiac disturbances (asystole, arrhythmias, episodic syncope, conduction block and cardiomyopathy) and hypogonadism (with elevated FSH). Early-onset male frontal balding is found in 20 – 50% of patients. Serum CK (typically less than 5x the upper limits of normal) and g-GT are usually elevated. Diabetes is found in 23% and abnormal glucose tolerance testing shows insensitivity in 75% of patients. Muscle biopsy (vastus lateralis) is abnormal even with normal manual strength testing being normal. The disorder is linked to the DM2 locus at chromosome 3q21. Lack of mental retardation in juvenile cases, less symptomatic distal, facial and bulbar weakness and less pronounced atrophy differentiates this form of dystrophy from DM1. While distal weakness and myotonia are usually the first complaints in DM1, muscle pain, stiffness, fatigue or proximal weakness are the reasons for seeking medical advice in PROMM.

Emery-Dreifuss muscular dystrophies (EDMD): This disorder can be either X-linked recessive (mutation emerin gen locus Xq28) or autosomal dominant (mutation lamin A/C gene locus 1q21.2-q21.3). The age of onset is usually in the first two decades, with mild contractures, delayed developmental milestones (walking at the age of >3 years), not being able to keep pace. The key features consist of familial myopathies associated with neck extensor and limb joint contractures (elbow, heel), humeropelvic-predominant weakness, cardiomyopathy, and cardiac arrhythmia (conduction system disease).  There is no hypertrophy. Weakness affects first the upper arm and pectoral girdle muscles and later the pelvic girdle and distal muscles of the lower extremities. Occasionally, facial muscles are affected. Serum CK are moderately elevated (2-4x). EMG shows features of myopathy but non-specific with myotonic discharges and echocardiogram reduced ejection fraction. DNA studies for dystrophin Xp21.2 gene deletion, fascioscapulohumeral 4q35 deletion, and EDMD-XR gene mutation should be negative. Sudden death is a frequent occurrence.

Facioscapulohumeral muscular dystrophy (FSHMD): FSHMD is one of the most frequent forms of muscular dystrophy (prevalence 1/20,00-100,000). The transmission is autosomal dominant with variable expression. In most patients weakness develops in the 2^nd and 3^rd decades. Weakness (and atrophy) of facial (whistling, inability to close eyes firmly, drinking through straw) and shoulder girdle muscles (raising arms above head, winging of the scapulae) are the first manifestations, followed by involvement of the peroneal (drop foot) and hip girdle muscles. Pseudohypertrophy is rare. There is rarely cardiac involvement and mental function is normal. A variant of FSHMD the early onset and rapidly progressive form called Coats disease associated with of high-frequency sensorineural hearing loss, retinal telangiectasias and detachment. In FSHMD, CK levels are either normal or increased (up to 5x baseline). Progression is usually slow and about 20% will become wheelchair bound. The gene locus of FSHMD is mapped to chromosome 4q35 (negative in 10% of patients). DNA testing is the preferred diagnostic test and may omit the necessity for EMG and biopsy.

Limb-girdle muscular dystrophy (LGMD): The LGMD diagnostic criteria are the following: face-sparing, slowly progressive predominant proximal symmetric weakness with primarily lower limb onset, normal to mildly raised serum CK activity, myopathic EMG and dystrophic changes on muscle biopsy. Cardiac involvement is infrequent. The age of onset varies from late childhood to early adulthood. Fourteen genetically distinct forms of LGMD have been identified the majority of LGMD are autosomal recessive (LGMD2) the others autosomal dominant (LGMD1). Major differential diagnosis of LGMD is X-linked recessive dystrophinopathies, FSHMD and EDMD.

The most important autosomal recessive forms presenting in adulthood are:

1) calpainopathy (CAPN3 gene chromosome 15q15)(LGMD 2A) Described in the Amish population, Réunion and Brazil. Age of onset usually between 8 - 15 years (range 2-40 years). The disorder is clinically characterized by early contractures of Achilles tendon (tendency to toe walk), proximal shoulder weakness with scapular winging, adductor weakness, difficulties in running and walking, and atrophic calves. Serum CK levels are very high (>10x increased). Patients are wheelchair bound after 10-28 years (mean age of 30). The diagnosis is based on Western blotting or molecular testing (immunostaining of muscle biopsy is unreliable).

2) dysferlinopathy (LGMD 2B) arises from the same gene (chromosome 2p13) as Miyoshi myopathy. The disease has been identified in Palestinian and Sicilian families. Clinically it can present as proximal or distal muscle leg weakness with difficulties in running and walking, inability to toe walk. Age of onset varies between 17-23 years. Serum CK levels are extremely high. The diagnosis is based on Western immunoblotting on muscle biopsy for dysferlin protein. Important differential diagnosis is polymyositis. Therefore any patient with polymyositis not responding to steroids should be considered as probable dysferlinopathy.

3) telethoninopathy (LGMD 2G gene chromosome 17q11) is clinically characterized by foot drop with difficulty in running and walking. It affects proximal muscles of both upper and lower limbs. The age of onset is in the early teens. Serum CK levels are substantially increased. Patients are wheelchair bound after 18 years. The diagnosis is based on immunohistochemistry of muscle biopsy.

Adult autosomal dominant forms are:

1) LGMD 1A (myotilin gene chromosome 5q22.3-31.3), clinically characterized by proximal weakness of hip and shoulder girdles, dysarthric speech, tightened heel cords. The age of onset is around 27 years. Serum CK values are markedly elevated. DNA testing is the only diagnostic modality.

2) LGMD 1B (chromosome 1q11)(similar to Bethlem myopathy (chromosome 21q)) Early manifestations are non-disabling contractures of elbows, ankles, interphalangeal joints of the fingers later followed by proximal symmetric weakness in the lower limbs. Very important here are the cardiac irregularities (e.g. arrhythmias, conduction block, etc.). Serum CK values are normal or slightly elevated. This form can be differentiated from EDMD by absence of contractures in neck and spine. Unlike in LGMD 1B, patients with Bethlem myopathy do not have cardiac involvement.

3) LGMD 1D (chromosome 6q23) patients suffer significant cardiac involvement and proximal symmetric weakness in the lower limbs. The age of onset is before 25 years. Serum CK values are slightly elevated (2-4x). There is no diagnostic test available.

Becker muscular dystrophy: This form of dystrophy is considered to be a late onset-form of Duchenne muscular dystrophy. It occurs in about 4/100,000 male births. It is a X-linked genetic disorder practically limited to males and transmitted by females. The age of onset is varies between 5 to 45 years. It results in proximal weakness first affecting the pelvic girdle then the pretibial muscles (foot drop), and later on the pectoral muscles and upper limbs. Hypertrophy of the calves, quadriceps femoris and deltoid muscles is a consistent finding. Cardiac involvement occurs and mentation is normal. Serum CK levels are 25 to 200 x increased. EMG shows a myopathic pattern with myotonic discharges. The latter together with muscle biopsy (ELISA dystrophin measurement) should be able to differentiate this disorder from hereditary spinal muscular atrophy. Patients become wheelchair bound before the age of 30 years, but some patients live an advanced age. Female carriers (mothers of the patient) have generally calf hypertrophy, raised serum CK levels and abnormal EMG.

Central core myopathy (CCM): Although mostly occurring in childhood, late onset forms exist. This autosomal dominant disorder presents often with mild and proximal weakness and muscle cramps following exercise. There are no fasciculations or myotonia. Pes cavus, pes planus and kyphoscoliosis may occur at young age. Serum CK levels may be normal or slightly increased. EMG shows small amplitude motor unit potentials with a normal interference pattern. The findings on muscle biopsy are pathognomonic. Malignant hyperthermia is the most common complication. The gene is located at chromosome 19q13.1. The disease is often mistaken for LGMD.

Nemaline myopathy: In patients with an adult-onset form of nemaline myopathy, there is often no family history and no symptoms preceding the onset of proximal and distal weakness in the 3^rd to 6^th decades (mean age 45 years). Nemaline myopathy occurs also in secondary myopathies such as HIV or drug-induced myopathies. Weakness affects predominantly proximal muscles in the upper limbs and later distal weakness in the lower extremities causing foot drop unresponsive to steroids. Adult woman may complain of fatigue or weakness during pregnancy. No bulbar symptoms are involved. Pes cavus or clubfoot may be seen at younger age. EMG is myopathic and CK may be normal or slightly elevated. Muscle biopsy (quadriceps femoris) is pathognomonic (modified Gomori trichrome technique), but the presence of nemaline rods alone is insufficient for a diagnosis of nemaline myopathy, these structure rarely may be seen in a number of other neuromuscular disorders, including mitochondrial myopathies, polymyositis, SMA, and acute alcoholic myopathy. Electron microscopy reveals accumulation of the rods with localized enlargement and streaming of the Z lines. Several loci have been identified (1q21 NEM1 locus - autosomal dominant form), 2q21.2 (NEM2 locus - autosomal recessive form), and 1q42). Respiratory failure is the most common cause of death. The need for intermittent or permanent use of a mechanical ventilator should be evaluated at an early stage because of the risk of nocturnal hypoxia and sudden respiratory failure.

Polymyositis: Polymyositis is characterized by subacute or chronic proximal symmetric weakness affecting usually the lower extremities more than the upper (including neck muscles “head ptosis”). Myalgia is generally present. 25% of patients have dysphagia. ESR is increased, and serum CK levels are highly elevated (50x normal value). However the absence of elevated serum CK levels does not exclude the diagnosis. EMG shows myopathic changes and occur earliest in paraspinal muscles. Muscle biopsy is the most specific diagnostic test.

Dermatomyositis: This disorders presents more acutely and is more frequently associated with systemic disease. Characteristic skin features include erythematous dermatitis involving the neck, upper trunk, and extensor surfaces of the proximal interphalangeal and metacarpophalangeal joints, elbows, and knees. Heliotrope discoloration of the upper eyelids and periorbital edema. Unlike polymyositis, dermatomyositis is highly associated with cancer or multisystemic disease.

Centronuclear myopathy (CNM): A mild autosomal dominant form of this disorder exists in adults and presents often with mild symmetric limb-girdle weakness and occasional diffuse muscle hypertrophy. The sporadic form and recessive autosomal form starts at a younger age. Ophthalmoparesis (limitation of upgaze) and more commonly ptosis are the presenting manifestations. Achilles contractures and muscle hypertrophy may be observed. Serum creatine kinase (CK), ECG, and echocardiogram are invariably normal. EMG shows a myopathic pattern. Muscle biopsy is diagnostic. The molecular basis of the autosomal forms of CNM is still unknown.

Tubular aggregates myopathy (TAM): This myopathy may present as a slowly progressive limb-girdle weakness and is transmitted as an autosomal dominant or recessive disorder. Muscle biopsy is diagnostic.

Myofibrillar myopathy: This disorder is most commonly inherited in an autosomal dominant pattern, but other patterns exist. The diagnosis of this disease is usually made by biopsy in adulthood. Slowly progressive weakness of the muscles of limbs and trunk is the main clinical feature. Both proximal and distal muscles are affected, more in the legs than arms. Cardiac abnormalities are found in 50% of patients.

Chronic thyrotoxic myopathy: Mostly middle-aged men are affected. The onset is insidious and the weakness progresses over weeks to months and is mild to moderate (rapid progression is difficult to differentiate from progressive SMA). The features are progressive weakness and wasting mostly of proximal muscles (pelvic girdle and thighs) occurring in conjunction with overt or masked hyperthyroidism. Bulbar muscles can be affected. The thyroid disease is usually chronic and the goiter is of nodular type. Signs of hyperthyroidism (exophthalmos) are not necessarily present. Serum CK levels as well as EMG, muscle biopsy may be normal. MG can be added to hyperthyroidism or the opposite.

Hypothyroid myopathy: This consists of action myospasm and myokymia and of precussion myoedema and slowness of both contraction and relaxation phases of tendon reflexes. Serum CK levels are usually elevated. Although not true myotonia EMG may show myopathic pattern with bizarre high-frequency discharges. Biopsy is not very helpful.

Chronic alcoholic myopathy: This is a painless weakness and atrophy affecting the proximal muscles of the limbs particularly the legs.

Hypophosphatemic myopathy

Acute

Acute steroid myopathy (critical illness myopathy): This type of myopathy occurs typically in intensive care units and often in patients with severe intractable asthma receiving high doses of corticosteroids. The use of neuromuscular blocking agents plays an important complementary role in its pathogenesis. The severe muscle weakness becomes evident when the systemic illness subsides, and slows weaning from the ventilator. The weakness is typically symmetric and diffuse, affecting the proximal and distal muscles as well as neck flexors and facial muscles. Tendon reflexes are normal or reduced and there may be confounding CIP. Serum CK levels may be increased, EMG shows features of myopathy. Muscle biopsy may be helpful in the diagnosis. Recovery may take weeks. 

Acute idiopathic demyelinating polyneuropathy or Guillain-Barré syndrome (GBS): The incidence is in the order of 1/100,000 people per year. The mean age of onset is around 40 years with a bimodal distribution, one in the 3 rd and one in the 6^th decade. About 90% of patients present with clinical preceding infections (influenza-like, respiratory (40%), gastrointestinal (20%)) 1- 3 weeks before the onset of neurologic symptoms. In 70% serologic positive infections are detected (Campylobacter jejuni, CMV, EBV, Mycoplasma pneumoniae, HIV, Lyme disease). The disease presentation can be different according to the type of organism involved: Campylobacter infections are associated with preceding diarrheal illness in 70% and present as a pure motor disorder (acute motor axonal neuropathy) with more severe course. CMV occurs in younger patients with a high occurrence of respiratory muscle weakness, cranial nerve involvement, and sensory involvement. GBS can occur irrespective of treatment of the underlying campylobacter infection. Cases of GBS have been reported following surgery or trauma, pregnancy, connective tissue diseases, medications (d-penicillamine), swine influenza virus vaccination or with underlying Hodgkin lymphoma. HIV-induced GBS occurs around the time of the primary infection. HIV antibodies may not be present and P24 antigen assay may be required to confirm the diagnosis. Neurologic symptoms develop 1 - 4 weeks after the preceding infection. The first neurological features are paresthesias in the toes, simultaneously or shortly thereafter followed by profound progressive motor weakness of more than one limb. In addition 50% of patients develop severe back and buttock pain which resolves as recover starts. Impaired posterior column functions and mild to severe sensory nerve involvement can be found. Symmetric muscle weakness with areflexia affecting most prominently the trunk musculature usually starts in the legs and ascends to the arms. Maximal muscle weakness (tetraparesis) develops within two weeks of the onset of neurologic symptoms and as per criterion symptom progression should not go beyond 4 weeks. Those patients who become bed-bound and ventilator-dependent within 5 days tend to have the most prolonged disability and sequelae. 50% of patients develop cranial nerve palsies, most commonly facial, bulbar, masticator and ocular muscles. Several degrees of respiratory muscle involvement may occur; 25% of patients need assisted ventilation. All patients with vital capacity <1L will need ventilation. Cardiac arrhythmias (10%), wide fluctuations in blood pressure and heart rate, episodes of facial flushing, pupil abnormalities, patchy anhidrosis, paralytic ileus or urinary retention. These are generally associated with poor prognosis. Other uncommon neurologic manifestations may be papilledema, optic neuritis and pyramidal signs and probably indicate associated ADEM. In 3% of cases GBS may be relapsing each time preceded by infections or vaccinations and needs to be differentiated from CIDP. Variants of GBS exist: bifacial paresis, pharyngeal-cervical-brachial weakness, MFS, paraparesis variant, autonomic form. CSF shows in 80% of patients typical albuminocytologic dissociation but may be absent the first few days (protein levels > 2g/l with no pleocytosis). The CSF protein content is highest during the 1^st and 3^rd week after the onset of symptoms.  Interestingly, in HIV-induced GBS CSF may show pleocytosis (20-30 cells/mm³). Serum IgM antibodies may be detected and stool cultures may be positive in case of Campylobacter jejuni enteritis. Antiganglioside polyclonal IgG antibodies (GM₁, GM₂, GD_1a, GQ_1b) are found 60% of patients. Mild forms are characterized by striking absence or 10 Comic Sans MS lower frequency rate of these findings, e.g. antiganglioside antibodies are almost absent in mild forms of AIDP. Earliest abnormalities on needle examination are reduced recruitment. Abnormalities in motor nerves are generally found during week 3, while those for sensory nerves in week 4. The neurophysiologic criteria requires 3 of the following 4 features: (1) reduction in NCVs in > 2 motor nerves, (2) conduction block or abnormal temporal dispersion in > 1 motor nerves, (3) prolonged distal latencies in > 2 motor nerves, (4) absent or prolonged F wave latencies in > 2 motor nerves. Improvement in motor amplitudes corresponds to clinical improvement, while conduction velocity and clinical examination are not closely related to one another. MRI might show enhancement of the cauda equine roots after gadolinium administration. Despite intensive efforts mortality is around 10%. Elderly succumb to cardiac complications, pulmonary embolism or chest infections. In the survival group 60% make full recovery. Factors of poor predictive outcome are: age >60 years, preceding diarrheal illness, development of severe paralyses within 5 days of the onset, respiratory failure requiring ventilation, and mean distal CMAP < 20% of normal. Observation of the patient is essential. When signs of oropharyngeal weakness, inability to walk or reduced vital capacity (<1L) occur plasma exchange or iv immunoglobulin should be considered. Both proved to have similar effectiveness. Relapse may be observed (days or 3 weeks) in 5-10% of patients who initially improved on either therapy. Mortality is up to 5%. GBS should be differentiated from acute spinal cord compression (cervical myelopathy), transverse myelitis, basilar artery thrombosis, HIV myelitis (usually at time of seroconversion and is associated with CSF pleocytosis), MG, acute intermittent porphyria, poliomyelitis (fever at onset and CSF pleocytosis), acute toxic neuropathies, botulism, tick paralysis, CIP and diphtheric neuropathy.

Chronic inflammatory demyelinating sensorimotor polyneuropathy (CIDP): This slowly progressive steroid-dependent polyneuropathy can occur at any age (mean age of onset in the 5^th decade). The clinical presentation is that of progressive/relapsing and remitting muscle weakness present for more than 2 months, symmetrical proximal and distal extremity weakness and hyporeflexia. May resemble GBS with the difference that there is no recovery but rather deterioration. In women, relapses are particularly associated with 3^rd semester of the pregnancy or immediately postpartum. Up to 30% of patients have a history of viral infection or vaccination. The majority of patients present with relative symmetric numbness and tingling (sensorimotor neuropathy with (sometimes painful) paresthesia), loss of vibratory sensation and joint position sense with positive Romberg sign as common early manifestations. Limb weakness is usually affecting proximal, muscles more than distal musculature. Both upper and lower extremities are involved, although the legs are usually affected more severely. Deep tendon reflexes are absent or depressed. Neck flexor weakness distinguishes CIDP from most other neuropathies. Sensory findings are typically mild and often include impaired touch and vibratory sensation, with less involvement of small-fiber sensation (pain and temperature). Deterioration over > 8 weeks is a distinguishing criterion from GBS. Cranial nerves (diplopia, dysphagia, facial or masticatory muscles, papilledema) are affected in about 15% of patients. A coarse, irregular action tremor, often seen in paraproteinemic neuropathy, may occur and may be related to a CNS equivalent mimicking neuroradiologically MS. Albuminocytologic dissociation (elevated CSF protein >45 mg/dl in the absence of a high cell count <10) is characteristic of CIDP. An elevated IgG index and IgG synthesis rate is consistent with the immune-related nature of CIDP. An elevated Q-albumin shows an impairment of the blood-brain barrier, which in CIDP is at the level of the inflammed nerve root sheaths within the thecal sac. The hallmark of the disorder is: 1) reduction of in NCV in >2 nerves  (<75% of normal); 2) partial conduction block (<15% change in duration between proximal and distal sites) or abnormal temporal dispersion (>15% change in duration between proximal and distal sites) in > 1 nerve; prolonged distal motor latencies in >2 nerves  (>130% of normal); absent or prolonged F-wave latencies in >2 nerves. In addition, distal CMAP duration > 9 msec for any of four motor nerves (ulnar, median tibial or peroneal nerve) increases the diagnostic sensitivity. SNAP are usually reduced or absent. Despite these criteria diagnostic difficulties may arise with borderline cases. CSF protein is normal or elevated (> 100 mg/dl). MRI findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy include enhancement (hypertrophy) of cervical roots, brachial plexus or the cauda equina, and may enhance after the administration of gadolinium. Sural nerve rarely adds to the diagnosis. A proven diagnosis of CIDP is an excellent chance of recovery with immunosuppresive therapy. CIDP can be associated with a variety of underlying disorders including: malignancies (lymphoma, Castleman disease, carcinoma), autoimmune disorders (SLE, temporal arteritis, RA, MCTD, amyloidosis etc.), infections (HIV infection before developing AIDS, hepatitis), renal disorders or endocrine disorders (diabetes, thyroid disorders). Suspicion of such relation should be raised when; (1) the neuropathy evolves rapidly with unusual features (e.g. extensive cranial nerve involvement or neuropathic pain), (2) deterioration continues despite immunosuppresive therapy.  Without therapy, CIDP is fatal in up to 10% of patients. Treatment (oral steroids, plasma exchange, i.v. immunoglobulin) should not be postponed until it is clear whether a patient suffers from GBS or CIDP. Although 95% of patients will show initial improvement following immunosuppressive therapy, the relapse rate is high. 64% improved and are able to return to work and 11% become bedridden or wheelchair bound.

Proximal diabetic neuropathy: This neuropathy is most commonly observed in NIDDM patients in their 6^th or 7^th decade. In contrast to diabetic polyneuropathy is seldom accompanies with diabetic retinopathy and nephropathy. The initial manifestation is usually subacute evolving asymmetric anterior thigh muscle pain. The pain has usually a deep, aching character with superimposed lancinating jabs, and often nocturnal in occurrence. Pelvic girdle and thigh muscle weakness and atrophy are evident, but mainly affecting the quadriceps muscle and developing over the next few days or weeks. The knee jerks are lost. Despite the unilateral onset, bilateral weakness eventually occurs in 50% of patients. The plantar responses may be extensor! The neuropathy is associated with profound weight loss. Femoral NC is delayed. CSF is slightly elevated. Improvement of the condition is usually seen after some months. Only 20% of patients have complete recovery of muscle strength. 1/5^th of patients experience recurrence.

Alcoholic myopathy: This is a painless predominantly proximal weakness which develops over days of weeks in the course of a prolonged drinking bout and is associated with hypokalemia. It is often preceded by vomiting. This form needs to be differentiated from the painful, myopathy with muscle tenderness and edema of the muscles of the trunk and limbs, accompanied by renal damage and hyperkalemia. Serum CK levels are highly elevated. It occurs in association with drinking bouts.

 Distal weakness

Acute

Chronic

Debrancher enzyme deficiency type III or Forbes-Cori disease (DED3): The clinical appearance of this autosomal recessive (chromosome 1p21) myopathy is highly variable. In the adult forms (starting in the 3^rd and 4^th decade) we differentiate several phenotypes: (1) muscular symptoms in adult years while the liver symptoms start in childhood, (2) muscle weakness starting in adult years long after liver symptoms in childhood have remitted, (3) only muscular symptoms as adults without any sign or history of liver dysfunction since childhood. Rapid fatigue and aching of muscles is a common presentation, occurring at exertion and beginning at an early age. The myopathy can also have different forms: (1) adult onset distal myopathy (distal leg weakness and intrinsic hand muscles); (2) subacute myopathy of the respiratory muscles; (3) severe generalised myopathy; and (4) minimal variant myopathy. Exercise intolerance is uncommon. Rarely, a mild polyneuropathy may be observed. The clinical course is complicated by advanced liver dysfunction and by severe cardiomyopathy. All patients have raised CK concentrations (up to 800 U/l), myogenic and neurogenic (denervation) features with pseudomytonic discharges on EMG, and markedly decreased debrancher enzyme activities in muscle or liver biopsy specimens. Leucocyte glycogen debrancher enzyme assay provides the diagnosis.

Phosphorylase b kinase deficiency (PBKD): Muscle-specific phosphorylase b kinase deficiency is an unusual autosomal recessive glycogen storage disorder (chromosome 16q12-13 or 7p12). The majority of patients are male with an age at diagnosis between 15 - 46 years. Clinical features include exercise intolerance, cramps, stiffness, myalgia (with myoglobinuria) and progressive, predominantly distal muscle weakness with atrophy. Serum CK levels may be increased. A forearm ischemic exercise test may show increased lactate production. The demonstration of reduced muscle, erythrocyte or liver phosphorylase b kinase activity by biochemical assay confirms the diagnosis.

Nemaline myopathy: In patients with an adult-onset form of nemaline myopathy, there is often no family history and no symptoms preceding the onset of proximal and distal weakness in the 3^rd to 6^th decades (mean age 45 years). Nemaline myopathy occurs also in secondary myopathies such as HIV or drug-induced myopathies. Weakness affect predominantly proximal muscles in the upper limbs and later distal weakness in the lower extremities causing foot drop unresponsive to steroids. Adult woman may complain of fatigue or weakness during pregnancy. No bulbar symptoms are involved. EMG is myopathic and CK may be normal or slightly elevated. Muscle biopsy (quadriceps femoris) is pathognomonic (modified Gomori trichrome technique), but the presence of nemaline rods alone is insufficient for a diagnosis of nemaline myopathy, these structure rarely may be seen in a number of other neuromuscular disorders, including mitochondrial myopathies, polymyositis, SMA, and acute alcoholic myopathy. Electron microscopy reveals accumulation of the rods with localized enlargement and streaming of the Z lines. Several loci have been identified (1q21 NEM1 locus - autosomal dominant form), 2q21.2 (NEM2 locus - autosomal recessive form), and 1q42). Respiratory failure is the most common cause of death. The need for intermittent or permanent use of a mechanical ventilator should be evaluated at an early stage because of the risk of nocturnal hypoxia and sudden respiratory failure.

Distal SMA: The age of onset is variable but generally before the age of 20 years. Autosomal recessive and dominant forms exist. The disease presents with distal weakness affecting the lower limbs more than the upper limbs (e.g. peroneal muscular atrophy with flaccid foot drop). Unlike in HSMN, nerve conduction studies are normal. Distal muscular dystrophy affecting the legs should be considered as another potential differential diagnosis. However the latter is easily identified since gastrocnemius muscles are preferentially affected and serum CK levels are tenfold increased. Life expectancy is normal. The disease is linked to 8p21 gene locus.

Uremic polyneuropathy: 50% of patients with end-stage chronic renal failure have clinical or electrophysiologic evidence of polyneuropathy. Uremic polyneuropathy develops gradually and occurs with glomerular filtration rates below 10 ml/min. In contrast to the underlying causes of renal failure, which are often resulting in focal or demyelinating polyneuropathy, uremic polyneuropathy is axonal in nature. Restless legs (burning paresthesias, itching sensation) are often the initial manifestation, followed by muscle cramps and fatigability and, finally, muscle distal weakness and atrophy. Autonomic features are impotence and postural hypotension (most marked at times of fluid removal by dialysis). The earliest objective signs are loss of vibration at the toes and absent ankle jerks. NCVs indicate axonal degeneration of motor and sensory fibers. Renal transplant greatly improves the condition. Occassionally an acute uremic polyneuropathy may develop that resembles GBS. Most patients are diabeteics in stable end-stage renal failure that is being treated with peritoneal dialysis. NCVs may show demyelinating features and raised CSF protein.

SCA-3 or Machado-Joseph disease: This is the most common SCA, accounting for 30-40% of ADCAs. It maps to chromosome 14q24.3-q32 (> 60-84 CAG repeats). Three clinical types of SCA-3 have been identified: (1) ALS-parkinsonism-dystonia form: onset before age 20 years and presents with limb weakness and spasticity affecting predominantly the legs and is associated in the majority of patients with ataxia and extrapyramidal signs (dystonia). Prominent pharyngeal weakness and spasticity with difficulty of speech and swallowing. Horizontal and vertical nystagmus and loss of fast saccadic eye movements and upward gaze is impaired. Peripheral neuropathy may occur. Fasciculations of face and tongue, without atrophy are common and early features. (2) Ataxic type: is the most common form. It begins in 2^nd or 4^th decade and consists of progressive cerebellar ataxia followed by with pyramidal and extrapyramidal deficits. As in type I, ophthalmoparesis, upward gaze deficits and facial and lingual fasciculations are also present. It needs to be differentiated from OPCA. (3) ataxic-ALS type: or late onset form (> 50 years) presents with pure cerebellar syndrome, distal sensory loss (all modalities) and distal amyotrophy (axonal sensory or sensorimotor polyneuropathy is found in 54% of the SCA-3 patients). No pyramidal, dementia or extrapyramidal findings occur. Patients are nonambulatory within 20 years after onset.

Welander distal muscular dystrophy (Welander DMD): Welander distal myopathy is an autosomal dominant disorder has its age of onset after 40 years. Early manifestations of weakness in small hand muscles and then spread to the distal leg muscles with foot drop. The course is mild and serum CK levels are increased up to 4x the normal values. The gene involved is located at chromosome 2p13. The variant form called late-onset distal myopathy the symptoms present in the reverse order and is associated with cardiomyopathy and heart failure. Another autosomal dominant form (tibial muscular dystrophy) presents first with foot drop and is also associated with increased serum CK levels (upto 4x the normal values). In the latter, the gene involved is located at chromosome 2p24. The course is mild.

Scapuloperoneal muscular dystrophy (ScPMD): This autosomal dominant disorder occurs in early adult life. Early manifestation is foot drop, followed by weakness of proximal arm muscles. The course is variable. The gene involved is located at chromosome 12.

Miyoshi distal muscular dystrophy (Miyoshi DMD): The age of onset varies from late childhood to early adulthood (mean age of onset 19 years). Pathognomonic for this myopathy is weakness arising focally in the peronei and calf muscles with very high serum CK values (10 to 100x normal). Later on, other muscles are involved such as proximal muscles of upper and/or lower limbs. The disease is inherited as an autosomal recessive disorder and arises from the same dysferlin gene (chromosome 2p12-14) as LGMD type 2B. DNA analysis is the preferred diagnostic test. Disease progression is slow.

Distal myopathy with rimmed vacuoles (DMRV): The age of onset of this distal myopathy ranges from 15-40 years. The characterist findings are: (a) weakness beginning in distal muscles in the legs, typically the anterior tibialis muscle and relatively sparing the quadriceps and upper limbs; (b) in advanced stage, generalized muscular wasting with sparing of the facial, extraocular, and intercostals muscles, and diaphragm; (c) normal or mild elevation of serum CK level; (d) mainly myogenic changes, with certain neurogenic features on EMG; and (e) rimmed vacuoles without obvious dystrophy on histopathology. The disease is autosomal recessif and caused by mutations in the GNE gene. This entity needs to be differentiated from Miyoshi myopathy and hereditary IBM. The patient becomes wheelchair-bound on average 12 years after the onset of the disease.

Inclusion body myositis (IBM): Sporadic IBM is the most common acquired inflammatory myopathy of patients over age 50 years (typically a late middle aged man), characterized by a slowly progressive, painless, asymmetric atrophy and weakness of both proximal and distal arm and leg muscles, most prominently affecting the finger and wrist flexors in the upper extremities and the quadriceps, and tibialis anterior muscles (ankle dorsiflexion) in the lower limbs (late stage drop foot). The most common clinical presentation is proximal weakness in the legs, and distal weakness in the arms. The esophagus is the most common (25-40%) organ affected, resulting in dysphagia and aspiration pneumonia. CK levels are usually mildly elevated (300 - 600 UI/L). EMG reveals myopathic disease with true myotonic discharges and sometimes associated mild sensorimotor distal axonal polyneuropathy. Muscle biopsy (myopathic alterations with inflammatory foci, rimmed vacuoles, inclusions which stain for amyloid, and ragged red fibers) confirms the diagnosis. T1 MRI of the arm may show hyperintensity indicating fatty replacement. The disorder shows poor response to immunosuppressive therapy. The most common pitfall in diagnosing IBM is polymyositis, dermatomyositis and MND.

Nonaka distal myopathy: The age of onset varies from late childhood to early adulthood (15-30 years). Pathognomonic for this myopathy is weakness arising focally in the anterior compartment of the lower leg with mild increase in serum CK values (1-5x normal values). The disease is inherited as an autosomal recessive disorder and arises from a gene located at chromosome 9p1. Disease progression is fast. The disease needs to be differentiated from the milder early onset distal myopathy which autosomal dominant (chromosome 14q) and occurs at an earlier age.

Desmin-related distal myopathies: These myopathies are autosomal dominant and occur between the age of 24-40 years. Early manifestations are usually distal leg and forearm weakness associated with cardiomyopathy. The course is generally severe. The genes involved are located at chromosomes 2q35 and 11q.

Myotonic dystrophy (DM1): MD type 1 is the most common form of adult muscular dystrophy (1/8,000). It is transmitted as an autosomal dominant trait. The severity of the disease is highly variable, with phenotypic spectrum including symptomatic or very mild affected adults. The following features are however constantly present: atrophy of the intrinsic hand muscles, facial muscle involvement, myotonia and dystrophic changes in nonmuscular tissue. In adulthood, it presents with myotonia, progressive muscle weakness and wasting affecting first distal limbs muscles or ptosis and facial weakness. Small muscles of the hands along with the extensor muscles of the forearms are often first to become atrophic. Alternatively, foot drop may be an early manifestation. Myotonia may precede the weakness by years and can be easily elicited (clinically and on EMG) in the hands and tongue after forceful contraction (action myotonia) or percussion. Typical facial appearance; hatchet-like shape of the head, frontal balding, slack eyes with ptosis, flat smile with facial and jaw weakness, and slightly forward carriage of head due to neck muscle weakness (“swan neck”). Pharyngeal and laryngeal weakness may result in monotonous nasal voice. IQ is low-normal with hostile, reticent, suspicious, uncooperative personality. Cardiomyopathy together with pneumonia (diaphragmatic weakness and alveolar hypoventilation) is the most frequent primary cause of sudden death occurring in 30% of patients. ECG changes consisting of major conduction changes, major arrhythmias or both are found in 26-48% of patients. Other characteristics dystrophic changes include lenticular opacities or cataract (slit lamp), dilatation and hypomobility of the esophagus or bowel (due to dilation), testicular and ovarian atrophy and daytime somnolence. Occassionally sensorimotor neuropathy, frontal hyperostosis and basal ganglia calcification may be found. The myotonic dystrophy locus (myotonin protein kinase or DMPK) is located on chromosome 19q13.3 (unstable trinucleotide CTG). Most patients are wheelchair bound in 20 years. If the genetic test is negative PROMM should be considered.

Central core myopathy (CCM): Although mostly occurring in childhood, late onset forms exist. This autosomal dominant disorder presents often with mild and proximal weakness and muscle cramps following exercise. There are no fasciculations or myotonia. Pes cavus, pes planus and kyphoscoliosis may occur at young age. Serum CK levels may be normal or slightly increased. EMG shows small amplitude motor unit potentials with a normal interference pattern. The findings on muscle biopsy are pathognomonic. Malignant hyperthermia is the most common complication. The gene is located at chromosome 19q13.1. The disease is often mistaken for LGMD.

Isaacs syndrome: The disease presents early in life with most patients being < 40 years of age at the time of symptom onset. A dominant mode of inheritance in the familial form of the disease may occur. Progressive painless stiffness, cramping, and weakness are prominent features of the disease. As opposed to fasciculations, patients complain of constant myokymia (writhing movements of the muscles under the skin visualized by continuous "rippling" movements of the muscle). These persist during sleep. Hyporeflexia is also seen in a large percentage of patients. Weakness, when present, tends to be in the distal lower extremities. Autonomic involvement may also be seen with hyperhidrosis and tachycardia. Calf hypertrophy has been described in some patients. "Action" or grip myotonia may be seen. However, percussion myotonia is rare. There may be an associated neuropathy. EMG is the most valuable diagnostic test with continuous motor activity: spontaneous discharges, and rhythmical and continuous firing. The configuration of the wave forms varies, representing either motor units or single fiber discharges. Myokymia is seen electrically. This motor activity persists during sleep. Serum CK levels may be increased. No routine laboratory test is available to detect the antibodies which have been described in research studies. The diagnosis is made by the characteristic history of cramping and stiffness, which persists during sleep and the EMG findings of continuous spontaneous discharges and myokymia in the affected muscle groups. SleepPlasma exchange can result in significant benefit, while the iv immunoglobulin can make symptoms worse.  The differential diagnosis includes stiff-person syndrome (prominent muscle stiffness which disappears during sleep with no myokymia on EMG). Anti-GAD antibodies are found in stiff-person syndrome. Benzodiazepines are helpful in stiff-person syndrome, but have no effect in Isaacs syndrome. Phenytoin and carbamazepine are helpful for stiffness in Isaacs syndrome, while there is no effect in stiff-person syndrome. Another disease to be considered in the differential is the Schwartz-Jampel syndrome (myotonia, stiffness syndrome, dwarfism and muscle hypertrophy).

Carpal tunnel syndrome (CTS): The prevalence of neurophysiologic confirmed, symptomatic CTS is about 3% among women and 2 % among men, with peak prevalence in women older than 55 years of age. The incidence in the general population is about 3‰. Early in the course, neurologic findings are reversible, and symptoms are intermittent. In one third of cases CTS is associated with medical conditions such as; pregnancy, inflammatory arthritis, SLE, amyloidosis, hypothyroidism, acromegaly, diabetes mellitus (6%), long-term dialysis and use of corticosteroids and estrogens. Furthermore occupational hazards are forceful and repetitive activities with hand and wrist (housewife, manufacturing, food processing, logging and construction work). History and physical examination have poor predictive value; pain, paresthesias and numbness in the territory of the median nerve, with typical nocturnal character or exacerbation; thenar atrophy and loss of two-point discrimination in the median nerve distribution occurs late in the course of the syndrome; two main physical signs, Phalen and Tinel sign have specificity and sensitivity all ranging between 40 - 80%. A frequently made mistake in diagnosis of CTS is the sensory loss over the palm of the hand (cutaneous palmar nerve) should be preserved since this nerve does not pass through the carpal tunnel. Comparison of median and ulnar sensory nerve conduction between wrist and ring finger (positive if latency difference >0.4 msec using a distance of  8 cm) has one of the highest sensitivities (85%) and specificities (97%). 10% of patients suspected of having CTS have normal electrodiagnostic studies. Alternatively, studying both motor and sensory wrist-palm conduction increases the diagnostic yield. The diagnostic accuracy of MRI is only moderate. Single injection of methylprednisolone (15 mg) locally in the carpal tunnel provides greater reduction in symptoms at 3 months than does a 10-days course of oral prednisolone (25 mg).

Facial weakness

Facioscapulohumeral muscular dystrophy (FSHMD): FSHMD is one of the most frequent forms of muscular dystrophy (prevalence 1/20,00-100,000). The transmission is autosomal dominant with variable expression. In most patients weakness develops in the 2^nd and 3^rd decades. Weakness (and atrophy) of facial (whistling, inability to close eyes firmly, drinking through straw) and shoulder girdle muscles (raising arms above head, winging of the scapulae) are the first manifestations, followed by involvement of the peroneal (drop foot) and hip girdle muscles. Pseudohypertrophy is rare. There is rarely cardiac involvement and mental function is normal. A variant of FSHMD the early onset and rapidly progressive form called Coats disease associated with of high-frequency sensorineural hearing loss, retinal telangiectasias and detachment. In FSHMD, CK levels are either normal or increased (up to 5x baseline). Progression is usually slow and about 20% will become wheelchair bound. The gene locus of FSHMD is mapped to chromosome 4q35 (negative in 10% of patients). DNA testing is the preferred diagnostic test and may omit the necessity for EMG and biopsy.

Myotonic dystrophy (DM1): DM type 1 is the most common form of adult muscular dystrophy (1/8,000). It is transmitted as an autosomal dominant trait. The severity of the disease is highly variable, with phenotypic spectrum including symptomatic or very mild affected adults. The following features are however constantly present: atrophy of the intrinsic hand muscles, facial muscle involvement, myotonia and dystrophic changes in nonmuscular tissue. In adulthood, it presents with myotonia, progressive muscle weakness and wasting affecting first distal limbs muscles or ptosis and facial weakness. Small muscles of the hands along with the extensor muscles of the forearms are often first to become atrophic. Alternatively, foot drop may be an early manifestation. Myotonia may precede the weakness by years and can be easily elicited (clinically and on EMG) in the hands and tongue after forceful contraction (action myotonia) or percussion. Typical facial appearance; hatchet-like shape of the head, frontal balding, slack eyes with ptosis, flat smile with facial and jaw weakness, and slightly forward carriage of head due to neck muscle weakness (“swan neck”). Pharyngeal and laryngeal weakness may result in monotonous nasal voice. IQ is low-normal with hostile, reticent, suspicious, uncooperative personality. Cardiomyopathy together with pneumonia (diaphragmatic weakness and alveolar hypoventilation) is the most frequent primary cause of sudden death occurring in 30% of patients. ECG changes consisting of major conduction changes, major arrhythmias or both are found in 26-48% of patients. Other characteristics dystrophic changes include lenticular opacities or cataract (slit lamp), dilatation and hypomobility of the esophagus or bowel (due to dilation), testicular and ovarian atrophy and daytime somnolence. Occasionally sensorimotor neuropathy, frontal hyperostosis and basal ganglia calcification may be found. The myotonic dystrophy locus (myotonin protein kinase or DMPK) is located on chromosome 19q13.3 (unstable trinucleotide CTG). Most patients are wheelchair bound in 20 years. If the genetic test is negative PROMM should be considered.

Myasthenia gravis (MG): The prevalence of MG in the general population is around 0.1‰. MG is a heterogeneous autoimmune disorder with regard to age of onset of disease, serum titers of anti-AchR antibodies, and severity of clinical symptoms. The disease predominates in women (affected twice as much as men) and most commonly peaks in the 2^nd - 3^rd decades, while the peak age in man occurs at later age 5^th - 6^th decade. In 5% of patients, MG is associated with other autoimmune diseases such as autoimmune thyroiditis, RA, SLE and pernicious anemia. In a large majority of patients (80‑90%) suffering from MG, these autoantibodies are found in the serum. MG is a monophasic illness, which begins relatively acutely in most patients (often following surgery, trauma, infection or pregnancy). The hallmark of MG is fluctuating weakness and muscle fatigability, particularly of ocular muscles (initially 40% and eventually 85%). Bulbar symptoms (dysphagia or dysarthria), leg weakness and generalized weakness with fatigue and muscle pain (low back pain) are found each in about 10% of patients. The pure ocular form of MG is observed in 15‑20% of patients. About 10-15% of MG patients have a thymoma. Two tests are of immediate diagnostic help in MG: the most direct confirmatory study is the edrophonium (Tensilon) test (sensitivity 80‑90%) and the repetitive supramaximal nerve stimulation (3 Hz) of the median nerve, which reveals a decremental response of the CMAP amplitude: in about 50% of MG patients a decrement (>10% decrease in CMAP amplitude of the 5^th potential vs. 1^st potential) to repetitive nerve stimulation is found. However in patients with pure ocular or mild generalized weakness the test is less likely to be positive. With regards to the edrophonium test, one or preferably two reliable endpoints (ptosis, dysconjugate gaze,...) must be taken as reference. Anti-AchR antibodies are found in 70-85% of all patients with generalized MG and around 50% of patients with the ocular form. The levels of the anti-AchR antibodies do not predict the severity or clinical course of the patient. Anti-AchR antibodies are almost invariable found in patients with both MG and associated thymoma. Patients with thymoma-associated MG, late age at disease onset (mean 65 years) and with intermediate titers of anti-AchR antibodies have high prevalence (55%) of anti-titin antibodies and anti-muscle-specific tyrosine kinase. Ryanodine receptor and anti-titin antibodies present in 70% and 95% of thymoma and 14% and 58% of late onset MG, respectively. The long‑term natural course of MG is highly variable. Generalization usually develops within the first year of the disease while spontaneous long-lasting remission occurs in 10‑15% of cases, usually in the first two years of the disease. Thymectomy is generally recommended for thymoma, moderate to severe MG inadequately controlled with pyridostigmine, and those patients <55 years. An estimated 75% of MG patients will benefit from thymectomy, and the intervention appears to be most efficient the first two years of the disease. Thymectomy is classically a long-term therapy and its effect may not be apparent until after 1 year. Thymectomy appears to increase the likelihood of long-term remission and possibly reduces the long-term exposure to immunosuppressive drugs. 80% of patients will respond favorable response to steroids. Corticosteroids (1mg/kg/d in 3 divided doses e.g. 20 mg tid or 120 mg alternate days) are used in patients with moderate to severe disabling symptoms that are refractory to pyridostigmine and require hospitalization due to risk of early exacerbation (first few days of therapy and lasting about 3-4 days or 2 weeks). However transient initial severe exacerbation (10% of patients) requiring mechanical ventilation or tube feeding may occur after 1 - 3 weeks. Maximum dose should be maintained until complete remission is accomplished (about 3 months), than tapering (5-10%/month) can begin. Steroid sparing can be envisaged with azathioprine (initially 1 mg/kg/day to a maintenance dose of 2-3 mg/kg/day). Short-term effects (1-2 months) are achieved with plasmapheresis and IVIg. Improvement starts within a few days after the onset of the treatment and is meaningful after 14 days, persisting at 1 month. Mostly patients with severe disease benefit from IVIg. In patients with Osserman classification grade > 2 plasmapheresis (5 sessions on alternate day basis over 1 week, each session removing 2.5-4 L of plasma to be replaced by 5% albumin in saline (ml/ml) including 1 L of fresh frozen plasma pre-thymectomy)) is indicated pre-thymectomy. Parameters such as fibrinogen, coagulation factors, calcemia should be monitored. Anticholinergic therapy should be continued tilt the morning of the intervention (1 mg iv or im neostigmine = 30 mg pyridostigmine po, e.g 1 mg iv q4h). Prednisolone 20 mg w or w/o cyclophosphamide 50 mg can be added if required pre-thymectomy. The post-operative dose of pyridostigmine is generally 25-50% of the pre-operative dose.  In acute cases, monitoring should be done by respiratory rate, pulse oximetry, FVC (intubation if FVC<15 ml/kg), arterial blood gases every 2 hours. Cranial neuropathies (diabetes and botulism, mitochondrial disorders, hypothyroidism, myopathies or MND), Wernicke encephalopathy, MFS, ALS, SMA, LEMS and drug-induced MG need to be excluded in the differential diagnosis. Congenital MG should always be considered in patients with seronegative MG, as in those cases there is a high prevalence of autoimmune conditions like thyroid disease, polymyositis, SLE, RA and pernicious anemia.

Oculopharyngeal muscular dystrophy (OPMD): A high prevalence occurs in some French-Canadian families and Bukhara Jews. The disorder is a late-onset autosomal dominant myopathy and is characterized by progressive eye muscle weakness, bilateral ptosis, and dysphagia and change in voice that usually start during 5^th or 6^th decades of life. Facial, hip, and shoulder weaken and become atrophic in later stages. Serum CK and aldolase levels are normal and EMG is positive only in the affected muscles. The gene locus has been mapped to chromosome 14q and DNA testing is now available.

Chronic progressive external ophthalmoplegia (CPEO): The age of onset is usually during the 2^nd and 3^rd decades of life. Pure CPEO presents with ptosis (often asymmetrical, weak opening and closure) and ophthalmoplegia (multidirectional limitation of eye movements affecting upward gaze maximally). Very often diplopia is absent or transient. The term CPEO plus is used when additional clinical features are present: such as retinitis pigmentosa, weakness and wasting of other muscles in 25% of cases (facial, sternocleidomastoideus, deltoids and/or peronei) and never precede the ophthalmological features, dysphagia, fatigue or exercise intolerance. Encephalopathic features may also occur with CPEO (dementia, seizures, myoclonus and stroke-like episodes. Seizures are however much less frequent than in other mitochondrial disorders. The disease leads to complete ophthalmoplegia with the eyes in central position. While blood mitochondrial DNA is usually normal, DNA extracted from muscle biopsy is always diagnostic and reveals single mitochondrial deletions in 70% of patients (sporadic cases). Other patients show maternal pattern of inheritance with mitochondrial DNA mutations (e.g. A3243G) or autosomal dominant or recessive patterns. Disability is mild except when coexisting CNS disease is present. Histological examination of muscle reveals ragged red fibers and a mosaic pattern of cytochrome c oxidase (COX) negative fibers. This OXPHOS mtDNA defect is often mistaken for MG, DM1 (myotonia, cataract, endocrine disturbances), FSHMD, KSS (abnormal growth and mentation, heart block, abnormal CSF) or OPMD.