**5. Myasthenia gravis subtypes and specific clinical situations**

**Ocular MG** (**OMG**). Myasthenic weakness that remains restricted to the ocular muscles for more than 2 years is defined as OMG [15] (**Figure 1**). Although most patients with OMG also present concomitant weakness of the orbicularis oculi muscles, this is not considered as evidence of generalization [5]. Remission may be seen in about 20% of these patients; however, it has to be noted that recurrences are possible even after 20 years [4, 5].

**Generalized MG** (**GMG**) can be further subclassified in early-onset (EOMG) and late-onset (LOMG) disease, with the cutoff age usually set at age 40. EOMG patients are more often women, typically presenting anti-AChR antibodies and thymus hyperplasia, while LOMG patients are more frequently male and have MuSK antibodies in addition to anti-AChR antibodies [1].

**MuSK-antibody myasthenia gravis** (**MuSK-MG**). MuSK antibodies have been reported in up to 50% of seronegative autoimmune MG cases [16] as well as in OMG [17]. MuSK-MG occurs predominately in women from adolescence through middle age [1, 5]. The anti-MuSK phenotype has a distinct clinical syndrome with prominent weakness in the cranial, bulbar, and respiratory muscles, frequently with moderate to severe atrophy of these clinically affected muscles (especially facial and genioglossus muscles) [1, 4, 5, 18]. Thus, the major complaints of these patients

**97**

ized assays [1].

**Figure 1.**

*Ocular myasthenia gravis.*

thymoma [1, 5, 6].

inhibitors [1, 5].

*Clinical Presentation of Myasthenia Gravis DOI: http://dx.doi.org/10.5772/intechopen.86566*

include dyspnea, nasal speech, and dysphagia leading sometimes to an important weight loss [2]. Some patients also present weakness of the neck extensor. Typically, there is little to no ocular muscle weakness and only a mild involvement of the limb muscles. It is important to mention that, in these patients, the myasthenic symptoms are more severe than in non-MuSK-MG individuals, with more frequent respiratory

**Seronegative MG** is defined by the absence of both anti-AChR and anti-MuSK antibodies ("double-seronegative MG"). These cases are clinically heterogeneous, but their frequency is particularly low. It has to be noted that some of these patients may have low-affinity anti-AChR antibodies that can only be detected using special-

**Thymoma-associated MG***.* Thymic pathology (thymic lymphofollicular hyperplasia and thymoma) occurs in 80–90% of MG patients and is typically milder in seronegative MG [20]. It was reported that over 10% of patients with MG have a thymoma and, conversely, that 35% of thymoma patients have MG [5]. Thymoma-associated MG, also termed paraneoplastic MG, is a seropositive MG subtype which occurs primarily after the third life decade and is equally frequent in males and females. Patients with this MG subtype have a more severe disease with lower rates of remission and higher mortality (30%) than patients without

**Transient neonatal myasthenia gravis** (**TNMG**) occurs in approximately 15% of infants born to mothers with autoimmune MG, as the anti-AChR antibodies get transferred across the placenta. The most common symptoms are feeble cry, ptosis, facial weakness, difficulty in feeding, respiratory weakness, and, in some cases, cyanosis. Rarely, affected infants present arthrogryposis (joint contracture) causing prolonged immobility in utero. It was found that the symptom severity in the newborn is not related to the severity of symptoms in the mother. These myasthenic manifestations resolve within the first month of life with acetylcholine esterase

**Juvenile myasthenia gravis** (**JMG**) is defined as the onset of immune-mediated

MG before age 18 [21] (**Figure 2**). These patients represent about 15% of the

crises [5]. In MuSK-MG thymic pathology is mostly absent or minimal [19].

*Clinical Presentation of Myasthenia Gravis DOI: http://dx.doi.org/10.5772/intechopen.86566*

*Thymus*

both.

possible even after 20 years [4, 5].

antibodies in addition to anti-AChR antibodies [1].

• **Class II**: Mild weakness affecting muscles other than ocular muscles; may also

○ **IIa**. Predominantly affecting the limb, axial muscles, or both. May also have

○ **IIb**. Predominantly affecting the oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of the limb, axial muscles, or both.

• **Class III**: Moderate weakness affecting muscles other than ocular muscles; may

○ **IIIa**. Predominantly affecting the limb, axial muscles, or both. May also have

○ **IIIb**. Predominantly affecting the oropharyngeal and respiratory muscles or both. May also have lesser or equal involvement of the limb, axial muscles, or

• **Class IV**: Severe weakness affecting muscles other than ocular muscles; may

○ **IVa**. Predominantly affecting the limb, axial muscles, or both. May also have

○ **IVb**. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal involvement of limb, axial muscles, or both.

• **Class V**: Defined as a state requiring intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in Class IVb [14].

**Ocular MG** (**OMG**). Myasthenic weakness that remains restricted to the ocular muscles for more than 2 years is defined as OMG [15] (**Figure 1**). Although most patients with OMG also present concomitant weakness of the orbicularis oculi muscles, this is not considered as evidence of generalization [5]. Remission may be seen in about 20% of these patients; however, it has to be noted that recurrences are

**Generalized MG** (**GMG**) can be further subclassified in early-onset (EOMG) and late-onset (LOMG) disease, with the cutoff age usually set at age 40. EOMG patients are more often women, typically presenting anti-AChR antibodies and thymus hyperplasia, while LOMG patients are more frequently male and have MuSK

**MuSK-antibody myasthenia gravis** (**MuSK-MG**). MuSK antibodies have been

reported in up to 50% of seronegative autoimmune MG cases [16] as well as in OMG [17]. MuSK-MG occurs predominately in women from adolescence through middle age [1, 5]. The anti-MuSK phenotype has a distinct clinical syndrome with prominent weakness in the cranial, bulbar, and respiratory muscles, frequently with moderate to severe atrophy of these clinically affected muscles (especially facial and genioglossus muscles) [1, 4, 5, 18]. Thus, the major complaints of these patients

**5. Myasthenia gravis subtypes and specific clinical situations**

have ocular muscle weakness of any severity.

lesser involvement of oropharyngeal muscles.

also have ocular muscle weakness of any severity.

lesser involvement of oropharyngeal muscles.

also have ocular muscle weakness of any severity.

lesser involvement of oropharyngeal muscles.

**96**

**Figure 1.** *Ocular myasthenia gravis.*

include dyspnea, nasal speech, and dysphagia leading sometimes to an important weight loss [2]. Some patients also present weakness of the neck extensor. Typically, there is little to no ocular muscle weakness and only a mild involvement of the limb muscles. It is important to mention that, in these patients, the myasthenic symptoms are more severe than in non-MuSK-MG individuals, with more frequent respiratory crises [5]. In MuSK-MG thymic pathology is mostly absent or minimal [19].

**Seronegative MG** is defined by the absence of both anti-AChR and anti-MuSK antibodies ("double-seronegative MG"). These cases are clinically heterogeneous, but their frequency is particularly low. It has to be noted that some of these patients may have low-affinity anti-AChR antibodies that can only be detected using specialized assays [1].

**Thymoma-associated MG***.* Thymic pathology (thymic lymphofollicular hyperplasia and thymoma) occurs in 80–90% of MG patients and is typically milder in seronegative MG [20]. It was reported that over 10% of patients with MG have a thymoma and, conversely, that 35% of thymoma patients have MG [5]. Thymoma-associated MG, also termed paraneoplastic MG, is a seropositive MG subtype which occurs primarily after the third life decade and is equally frequent in males and females. Patients with this MG subtype have a more severe disease with lower rates of remission and higher mortality (30%) than patients without thymoma [1, 5, 6].

**Transient neonatal myasthenia gravis** (**TNMG**) occurs in approximately 15% of infants born to mothers with autoimmune MG, as the anti-AChR antibodies get transferred across the placenta. The most common symptoms are feeble cry, ptosis, facial weakness, difficulty in feeding, respiratory weakness, and, in some cases, cyanosis. Rarely, affected infants present arthrogryposis (joint contracture) causing prolonged immobility in utero. It was found that the symptom severity in the newborn is not related to the severity of symptoms in the mother. These myasthenic manifestations resolve within the first month of life with acetylcholine esterase inhibitors [1, 5].

**Juvenile myasthenia gravis** (**JMG**) is defined as the onset of immune-mediated MG before age 18 [21] (**Figure 2**). These patients represent about 15% of the

**Figure 2.** *Myasthenic crisis in juvenile myasthenia gravis.*

autoimmune MG cases, being particularly uncommon in the first year of life. JMG is rarely associated with thymomas and has a high rate of spontaneous remission [1].

**Congenital myasthenic syndromes (CMS**) are caused by genetic (mostly autosomal recessive) abnormalities of the NMT, leading to fluctuating or persistent hypotonia of the ocular, bulbar, or limb muscles; in infancy it may cause arthrogryposis, delayed motor milestones, and unexplained apnea episodes. The weakness usually worsens during adolescence but then often stabilizes; however, prominent myopathy and scoliosis may be present [1, 4].

**Lambert-Eaton myasthenic syndrome** (**LEMS**). LEMS is a rare autoimmune disorder resulting from impaired release of ACh by the presynaptic terminal of the NM junction and in the autonomic ganglia. By definition, LEMS is associated with the presence of anti-presynaptic P/Q type voltage-gated calcium channels (VGCC) antibodies. Clinically, LEMS has an insidious onset - usually characterized by muscle tenderness - followed by progressive development of weakness and fatigue [1, 4, 5]. The most frequent symptoms found in LEMS include abnormal fatigue, weakness of the proximal muscles (particularly in the legs), hyporeflexia, and, dysautonomic manifestations (dry mouth, orthostatic hypotension constipation, and impotence). Some patients may present facilitation of strength after brief, isometric contraction and decline of strength after sustained activity. LEMS is classically associated with underlying malignancy or autoimmune disease. It was reported that in about 75% of men and 30% of women, this is a paraneoplastic condition accompanying in most of the cases (80%) a small cell lung cancer. The disease can also occur with other malignancies such as lymphoproliferative disorders, malignant thymoma, and rarely carcinoma of the breast, stomach, colon, prostate, and bladder [4, 5].

**Pregnancy**. MG may improve, worsen, or remain stable during pregnancy; however, a significant risk of deterioration in the puerperium was reported [1, 4]. Severe respiratory insufficiency can be triggered by the physical stress of labor and delivery; similarly, patients with eclampsia during pregnancy have a higher risk of complications of both conditions, considering, for example, that magnesium sulfate cannot be used in MG patients [5]. It should also be noted that a newborn

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*Clinical Presentation of Myasthenia Gravis DOI: http://dx.doi.org/10.5772/intechopen.86566*

is stable [1, 4] (**Table 2**).

MuSK-antibody myasthenia

Transient neonatal myasthenia gravis

Congenital myasthenic

Lambert-Eaton myasthenic

syndromes

syndrome

**Table 2.**

Seronegative MG • Rare

gravis

**Myasthenia gravis subtypes and specific clinical situations**

from a myasthenic pregnancy has a higher risk to develop TNMG (see above). Currently, women with MG are advised to delay pregnancy until after the disease

• Typically associated with anti-AChR antibodies

• Lower rates of remission and higher mortality

• High rate of spontaneous remission

Pregnancy • MG may improve, worsen, or remain stable during pregnancy

• May occur in infants born to mothers with autoimmune MG

• The myasthenic symptoms resolve within the first month of life with

• Caused by genetic (mostly autosomal recessive) abnormalities of the

• Women with MG are advised to delay pregnancy until after the disease

• Associated with anti-presynaptic P/Q type VGCC antibodies • Frequent symptoms: fatigue, weakness of the proximal muscles (particularly in the legs), hyporeflexia, and dysautonomic manifestations • Associated with underlying malignancy or other autoimmune disease

• Prominent weakness in the cranial, bulbar, and respiratory muscles • Myasthenic symptoms more severe than in non-MuSK-MG patients

**Notes**

Ocular MG • Weakness restricted to the ocular muscles Generalized MG • Subclassified in early-onset and late-onset MG

• Clinically heterogeneous Thymoma-associated MG • 80–90% of MG patients also present thymic pathology

treatment Juvenile myasthenia gravis • The disease onset occurs before age 18

NMT

is stable

*Myasthenia gravis subtypes and specific clinical situations—Summarized features.*

## *Clinical Presentation of Myasthenia Gravis DOI: http://dx.doi.org/10.5772/intechopen.86566*

*Thymus*

**Figure 2.**

autoimmune MG cases, being particularly uncommon in the first year of life. JMG is rarely associated with thymomas and has a high rate of spontaneous remission [1]. **Congenital myasthenic syndromes (CMS**) are caused by genetic (mostly autosomal recessive) abnormalities of the NMT, leading to fluctuating or persistent hypotonia of the ocular, bulbar, or limb muscles; in infancy it may cause arthrogryposis, delayed motor milestones, and unexplained apnea episodes. The weakness usually worsens during adolescence but then often stabilizes; however, prominent

**Lambert-Eaton myasthenic syndrome** (**LEMS**). LEMS is a rare autoimmune disorder resulting from impaired release of ACh by the presynaptic terminal of the NM junction and in the autonomic ganglia. By definition, LEMS is associated with the presence of anti-presynaptic P/Q type voltage-gated calcium channels (VGCC) antibodies. Clinically, LEMS has an insidious onset - usually characterized by muscle tenderness - followed by progressive development of weakness and fatigue [1, 4, 5]. The most frequent symptoms found in LEMS include abnormal fatigue, weakness of the proximal muscles (particularly in the legs), hyporeflexia, and, dysautonomic manifestations (dry mouth, orthostatic hypotension constipation, and impotence). Some patients may present facilitation of strength after brief, isometric contraction and decline of strength after sustained activity. LEMS is classically associated with underlying malignancy or autoimmune disease. It was reported that in about 75% of men and 30% of women, this is a paraneoplastic condition accompanying in most of the cases (80%) a small cell lung cancer. The disease can also occur with other malignancies such as lymphoproliferative disorders, malignant thymoma, and rarely carcinoma of the breast, stomach, colon, prostate, and

**Pregnancy**. MG may improve, worsen, or remain stable during pregnancy; however, a significant risk of deterioration in the puerperium was reported [1, 4]. Severe respiratory insufficiency can be triggered by the physical stress of labor and delivery; similarly, patients with eclampsia during pregnancy have a higher risk of complications of both conditions, considering, for example, that magnesium sulfate cannot be used in MG patients [5]. It should also be noted that a newborn

myopathy and scoliosis may be present [1, 4].

*Myasthenic crisis in juvenile myasthenia gravis.*

**98**

bladder [4, 5].

from a myasthenic pregnancy has a higher risk to develop TNMG (see above). Currently, women with MG are advised to delay pregnancy until after the disease is stable [1, 4] (**Table 2**).


#### **Table 2.**

*Myasthenia gravis subtypes and specific clinical situations—Summarized features.*

*Thymus*
