Neuromuscular Diseases

Questions

1. You have been following a patient in clinic for years for amyotrophic lateral sclerosis (ALS). Within the past few months, the family has noticed increasing behavioral and language changes, such as reduced speech output, trouble naming objects, and increased impulsivity. Repeat neuroimaging shows atrophy of the frontal and temporal lobes bilaterally. Mutations in which of the below genes are most likely to be found in our patient?

A. C9orf72

B. Fused in sarcoma (FUS)

C. Senataxin (SETX)

D. Superoxide dismutase 1 (SOD1)

E. Choices A and D

View Answer

1. Answer A. (MN-88) Mutations in the gene C9orf72 causing expansion nucleotide repeats are the most-common known causes of ALS and FTD. Mutations in C9orf72 can cause clinical phenotypes of ALS and/or FTD in affected individuals, leading to accumulation of abnormally phosphorylated and ubiquitinated TAR DNA binding protein 43 (TDP-43) in neurons of these patients (Table 12.1.1). Given the common pathological and genetic features found in both ALS and FTD, it is estimated that about half of all ALS patients have some degree of frontotemporal dysfunction.

TABLE 12.1.1 Amyotrophic Lateral Sclerosis-Associated Genes^a

Name	Site	Gene	Inheritance	Comment
FTD-ALS	9p21	C9orf72	AD	ALS and FTD Hexanucleotide expansion Most common cause of ALS
ALS1	21q22.1	SOD1	AD	Adult 15%-20% of familial ALS
ALS2	2q33	Alsin	AR	Juvenile; may resemble PLS
ALS3	18q21	—	—	—
ALS4	9q34	Senataxin (SETX)	AD	Juvenile; slow progression; allelic to CMT2
ALS5	15q15.1-q21.1	SPG11	AR	Juvenile Most common AR ALS Also seen in HSP
ALS6	16p11.2	FUsed in Sarcoma (FUS)	AD	Adult and juvenile onset
ALS7	20p13	—	AD	Adult
ALS8	20q13.33	VAPB	AD	Adult
ALS9	14q11.2	ANG	AD	—
ALS10	1p36.22	TARDBP	AD	Some with FTD
ALS11	6q21	FIG4	AD	Allelic to CMT 4J (AR)
ALS12	10p13	OPTN	AD/AR	—
ALS13	12q24.12	ATXN2	AD	CAG expansions and increased ALS risk Expansions also seen with SCA2
ALS14	9p13.3	VCP	AD	Mutations also seen with IBMPFD
ALS15	Xp11.21	UBQLN2	X-linked	Reduced penetrance in women
ALS16	9p13.3	SIGMAR1	AR	Juvenile
ALS17	3p11.2	CHMP2B	AD	May cause FTD
ALS18	17p13.2	PFN1 (Profilin 1)	AD	—
ALS19	2q34	ERBB4	AD	—
ALS20	12q13.13	HNRNPA1	AD	May cause multisystem proteinopathy
ALS21	5q31.2	MATR3	AD	Formerly distal myopathy 2, VCPDM
ALS22	2q35	TUBA4A	AD	ALS and FTD
ALS23	10q22.3	ANXA11	AD
ALS24	4q33	NEK1	AD
ALS25	12q13.3	KIF5A	AD	Adult Also seen in HSP
AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; AR, autosomal recessive; CAG, cytosine-adenine-guanine; CMT2, Charcot-Marie-Tooth hereditary neuropathy type 2; CMT4J, Charcot-Marie-Tooth neuropathy type 4J; FTD, frontotemporal dementia; HSP, hereditary spastic paraplegia; IBMPFD, inclusion body myopathy with Paget disease and frontotemporal dementia; PLS, primary lateral sclerosis; SCA2, spinocerebellar ataxia type 2; VCPDM, vocal cord and pharyngeal dysfunction with distal myopathy.
^aOther genes described and implicated in familial ALS-DAO, NEFH, HNRNPA2B1, SQSTM1/p62.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

2. A 55-year-old woman presents to your clinic for evaluation of worsening arm and leg weakness, difficulty walking, and fatigue. On examination, she is found to have wasting of her thenar and hypothenar muscles of each hand, along with reduced strength in all extremities with a left foot drop. You note fasciculations in her left quad, along with a jaw jerk, brisk upper-extremity reflexes with positive Hoffman’s sign, and reduced patellar reflexes. Nerve conduction studies (NCS) are unremarkable, and needle electromyography (EMG) shows diffuse fibrillations and chronic denervation in her upper extremity, diaphragm, and lower-extremity muscles. Which of the following statements is correct with regards to the patient’s most likely diagnosis?

A. The patient likely suffers from primary lateral sclerosis (PLS)

B. The patient likely suffers from progressive muscular atrophy (PMA)

C. The patient likely suffers from spinobulbar muscular atrophy (SBMA) or Kennedy Disease

D. The patient most likely suffers from amyotrophic lateral sclerosis (ALS)

E. The patient most likely suffers from multifocal motor neuropathy (MMN)

View Answer

2. Answer D. (MN-88) The patient above meets the revised El Escorial criteria for ALS with findings of upper-motor and lower-motor neuron signs in all four motor regions (cranial, cervical, thoracic, and lumbosacral). The NCS/EMG findings are consistent with ALS and do not support another disease process (Table 12.2.1). Patients with PLS have upper motor neuron signs only while those with PMA have lower motor neuron injury and pathology only (Table 12.2.2). Similar to PMA, patients with MMN should display purely lower motor neuron signs, although classically have conduction block on EMG and may have anti-GM1 antibodies. Kennedy disease or SBMA is secondary to a trinucleotide CAG repeat, and patients display prominent bulbar weakness with upper and lower motor neuron signs. Kennedy disease is X-linked recessive, thus unlikely to be seen in our female patient.

TABLE 12.2.1 Revised El Escorial Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis

Suspected ALS: a pure LMN syndrome in two or more regions
Possible ALS: UMN and LMN signs present together in one region or UMN signs alone in two or more regions or LMN signs rostral to UMN signs
Laboratory-supported ALS: UMN and LMN signs in one region or UMN signs alone in one region with LMN signs identified by EMG in two regions
Probable ALS: UMN and LMN signs in more than two regions, and some UMN signs must be rostral to (above) LMN signs
Definite ALS: UMN and LMN signs in three or more regions

All require absence of electrophysiologic or pathologic evidence of another disease process to explain clinical findings.

ALS, amyotrophic lateral sclerosis; EMG, electromyogram; LMN, lower motor neuron; UMN, upper motor neuron.

Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

TABLE 12.2.2 Motor Neuron Disease Variants

Amyotrophic lateral sclerosis (ALS)	Upper and lower motor neuron degeneration
Progressive muscular atrophy (PMA)	Purely lower motor neuron involvement
Primary lateral sclerosis (PLS)	Purely upper motor neuron involvement
Progressive bulbar palsy	Bulbar symptoms only or bulbar-onset ALS
Monomelic muscular atrophy	Lower motor neuron predominant, one arm
Bibrachial amyotrophy	Lower motor neuron predominant, both arms
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

3. You diagnose the above patient with amyotrophic lateral sclerosis (ALS). Which of the following treatment options would be most appropriate?

A. Refer to a multidisciplinary ALS center

B. Start edaravone infusion given its ability to slow the progression of ALS

C. Start modafinil for fatigue

D. Start riluzole given its survival benefit in patients with ALS

E. Choices A and D

View Answer

3. Answer A. (MN-88) Patients with ALS should be referred to an ALS center to receive care from a multidisciplinary ALS team. Advance care planning is an important aspect of disease management and requires expertise of multiple physician groups and social work. The rest of the choices are all possible options for care but should be considered in the broad context of the patient’s goals of care and treatment plan.

4. Which of the following agents can be considered for treatment of pseudobulbar affect (unpredictable, excessive, and exaggerated emotional response) in patients with amyotrophic lateral sclerosis (ALS)?

A. Clonazepam

B. Dextromethorphan-quinidine

C. Electroshock therapy

D. Pimavanserin

E. Quetiapine

View Answer

4. Answer B. (MN-88) Pseudobulbar affect is common in patients with ALS. Dextromethorphan-quinidine and selective serotonin inhibitors can be used to treat this condition. Pimavanserin is used to treat hallucinations and delusions in Parkinson disease. Antipsychotic medications, electroshock therapy, and benzodiazepines are not used to treat pseudobulbar affect.

5. A 74-year-old man with a history of poorly controlled diabetes and hyperlipidemia presents with an acute infarct of the left lateral medulla. You would expect the following on examination:

A. Contralateral ptosis

B. Ipsilateral loss of facial pain, light touch, and temperature sensation

C. Ipsilateral loss of facial pain sensation only

D. Ipsilateral loss of facial temperature sensation with preserved light touch and pain sensation

E. Ipsilateral loss of pain and temperature sensation in the trunk and limbs

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5. Answer B. (MN-89) A lateral medullary infarct causes ipsilateral limb dysmetria, ipsilateral Horner syndrome, impairment of ipsilateral facial pain, light touch, and temperature sensation, paralysis of the palate pharynx and larynx with dysphagia and dysphonia, and lateropulsion. Loss of facial pain, light touch, and temperature sensation is due to injury to the spinal tract of cranial nerve V. There is contralateral impairment of pain and temperature in the trunk and limbs, due to the involvement of the lateral spinothalamic tract.

6. A 36-year-old woman presents with recurrent episodes of severe, recurrent stabbing pains in the left cheek, which are easily triggered by brushing her teeth or a breeze of cold air over her face. Her neurological examination is normal. Which would be a first step in her treatment?

A. Recommend a night guard to be worn every night

B. Refer to neurosurgery for microvascular decompression

C. Start carbamazepine 100 mg bid and titrate up to a therapeutic response

D. Start injections of orobotulinum A

E. Start lamotrigine 25 mg daily and titrate up to a therapeutic response

View Answer

6. Answer C. (MN-89) The patient describes a classic story for trigeminal neuralgia. The American Academy of Neurology and European Federation of Neurological Societies guidelines recommend carbamazepine as first-line therapy for trigeminal neuralgia.

7. A patient presents with right-sided facial weakness. If his lesion is in the facial nerve between the geniculate nucleus and chorda tympani, which of the following would you expect?

A. Right facial weakness alone

B. Right facial weakness and impaired lacrimation

C. Right facial weakness, hyperacusis, oculomotor palsy, and dysphagia

D. Right-sided facial weakness, loss of taste in the right anterior two-third of the tongue, and impaired lacrimation

E. Right-sided facial weakness and loss of taste in the right anterior two-third of the tongue

View Answer

7. Answer E. (MN-89) In addition to facial weakness, there is loss of gustatory sensation because gustatory sensation travels via the chorda tympani. Innervation of the stapedius muscle is typically distal to the geniculate ganglion and proximal to the chorda tympani and may or may not cause hyperacusis in this scenario. Lesions distal to the geniculate ganglion do not cause impaired lacrimation. Dysphagia nor weakness of ocular movements themselves should not be present in an isolated injury to the facial nerve (see Figure 12.7.1 and Table 12.7.1).

FIGURE 12.7.1 (Reprinted with permission from Campbell WW. DeJong’s the Neurologic Examination. 6th ed. Lippincott Williams and Wilkins; 2005.)

TABLE 12.7.1 Clinical Manifestations of Lesions of the Facial Nerve

Location of Lesion	Motor Function	Gustatory Sensation	Lacrimation
At facial nerve nucleus in pons	Impaired	Impaired	Impaired
Origin of nerve/geniculate ganglion	Impaired	Impaired	Impaired
Between geniculate ganglion and chorda tympani	Impaired	Impaired	Spared
At stylomastoid foramen	Impaired	Spared	Spared
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

8. A patient presents with worsening left facial weakness and left unilateral hyperacusis. Symptoms started approximately 48 hours ago. Which of the following interventions has high-quality evidence supporting its use?

A. Starting a 10-day course of ophthalmic saline 4 times a day

B. Starting a 10-day course of oral acyclovir

C. Starting a 10-day course of oral prednisone

D. Starting a 10-day course of oral valacyclovir

E. Urgent referral for surgical decompression of nerve entrapment within the first 7 days of symptoms

View Answer

8. Answer C. (MN-89) The patient has Bell’s Palsy. A large randomized controlled trial demonstrated a higher percent of patients who had a good clinical outcome at 9 months among those who received a 10-day course of oral prednisone (94% vs 82%). There is weak evidence that valacyclovir may improve outcomes; however, this has not been substantiated in a large definitive trial. A small trial showed no benefit with the use of acyclovir. Small randomized controlled trials have attempted to study surgical intervention but have been similarly inconclusive. Conservative measures including the use of eye patches and ophthalmic saline are appropriate for patients who do not have complete eye closure, but these interventions have not been systematically evaluated.

9. A young man has a traumatic injury resulting in isolated compression of the lateral cord of the brachial plexus. Which group of muscles might be affected?

A. Biceps, deltoid, pectoralis major, pronator teres

B. Biceps, deltoid, pectoralis major, triceps

C. Biceps, deltoid, triceps, pronator teres

D. Flexor carpi radialis, biceps, pectoralis major, pronator teres

E. Pectoralis major, deltoid, biceps, flexor carpi radialis

View Answer

9. Answer D. (MN-90) The deltoid is innervated by the axillary nerve, and triceps are innervated by the radial nerve; both of these are derived from the posterior cord of the brachial plexus. All other muscles listed are supplied by the lateral cord of the brachial plexus and could be affected by this injury.

10. Which of the following statements regarding carpal tunnel syndrome is true?

A. Electrodiagnostic studies are not helpful to confirm the lesion or grade the severity

B. It may cause weakness and atrophy of the first dorsal interossei muscle

C. Tasks requiring high force and repetition, such as food processing, are a risk for developing carpal tunnel syndrome

D. The pain is typically worse in the morning

E. The worst pain is typically in the fifth digit of the hand

View Answer

10. Answer C. (MN-90) Tasks requiring high force and repetition are a risk factor. The worst pain in the carpal tunnel syndrome is typically in the digits 1 to 3 and the lateral side of digit 4, which is innervated by the median nerve. The fifth digit is innervated by the ulnar nerve. Sometimes there is pain that spreads to the entire hand, but the fifth digit is not the worst point of involvement. Pain from carpal tunnel syndrome is usually worse at night. The abductor pollicis brevis is one of the hand muscles innervated by the median and can have weakness and atrophy. The first dorsal interossei is innervated by the ulnar nerve and is not affected in carpal tunnel syndrome. Electrodiagnostic studies can localize the lesion of the median nerve to the wrist and grade the severity.

11. A 28-year-old woman has a normal pregnancy and spontaneous vaginal delivery. Twelve hours after delivery, she is recovering and first attempts to walk to the bathroom; she has a very unsteady gait and feels that her left leg is weak. On examination, she has focal weakness of the left hip flexion and absent left patellar reflex. Which nerve is involved?

A. Femoral nerve

B. Ilioinguinal nerve

C. Lateral femoral cutaneous nerve

D. Obturator nerve

E. Tibial nerve

View Answer

11. Answer A. (MN-90) The scenario describes a case of postpartum femoral neuropathy, typically caused by compression of the nerve at the level of the inguinal ligament during prolonged lithotomy position. Obturator neuropathy is also seen in this scenario but results in foot drop. Lateral femoral cutaneous nerve injury can also occur in the setting of childbirth but results in the isolated syndrome of meralgia paresthetica, resulting in lateral-thigh sensory symptoms.

12. Which of the following is a key characteristic of the acute motor axonal neuropathy (AMAN) variant Guillain-Barré syndrome, distinguishing it from more typical presentations of acute inflammatory demyelinating polyneuropathy?

A. Elevated CSF white count

B. Faster response to immunotherapies

C. Minimal demyelination

D. Normal CSF protein

E. Onset with oculomotor or bulbar weakness

View Answer

12. Answer C. (MN-91) Acute motor axonal neuropathy (AMAN) is a form of the clinical Guillain-Barré syndrome and typically shares some features including ascending paralysis and hyporeflexia and elevated CSF protein with typically normal CSF leukocyte count. In typical Guillain-Barré syndrome, nerve conduction studies principally demonstrate a demyelinating pattern. In AMAN, nerve conduction studies demonstrate direct axonal injury with little to no demyelination. Response to immunotherapy in AMAN is not faster; in many cases, response to treatment is less robust than demyelinating forms of Guillain-Barré syndrome.

13. Which of the following demyelinating polyneuropathies is most common in younger patients?

A. Anti-MAG neuropathy

B. Charcot-Marie-Tooth type 1A

C. Diphtheria

D. Guillain-Barré syndrome

E. Leprosy

View Answer

13. Answer B. (MN-91) Charcot-Marie-Tooth type 1A is caused by a duplication of the PMP22 gene and causes uniform demyelination; it is most commonly diagnosed in childhood or adolescence. The remaining etiologies are infectious, post-infectious, or spontaneous autoimmune processes and are more common later in life. The most common form of Guillain-Barré clinical syndrome in North American is acute inflammatory demyelinating polyneuropathy, which causes a multifocal demyelinating polyneuropathy. Leprosy causes an axonal neuropathy after direct infiltration of nerves from mycobacterium organisms. Antibodies against myelin-associated glycoprotein (MAG) typically cause a neuropathy, with distally accentuated demyelination. Diphtheria, which is an infectious cause of a demyelinating polyneuropathy, typically initially causes dysfunction of oculomotor nerves and pharyngeal control.

14. Which of the following treatments for hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) may not only stop disease progression but also have data suggesting the potential for clinical improvement in large trials?

A. Bone marrow transplant

B. Diflunisal

C. Liver transplant

D. Patisiran and inotersen

E. Tafamidis

View Answer

14. Answer D. (MN-91) Inotersen is an antisense oligonucleotide, and patisiran is a small interfering RNA, both of which reduce transthyretin production and have good evidence showing the potential for clinical improvement. A bone marrow transplant would not be effective for polyneuropathy associated with hATTR; it is an effective treatment for AL amyloidosis, caused by light chains. Carbamazepine is not used to treat hATTR. The other treatments listed have evidence that they may slow disease progression. Liver transplant is effective for some patients with hereditary transthyretin amyloidosis, since 95% of the mutated transthyretin is produced in the liver. Diflunisal and tafamidis stabilize the transthyretin tetramer, which reduces the formation of transthyretin monomers misfolding into amyloid and has shown efficacy for the polyneuropathy in hATTR.

15. A 12-year-old boy is diagnosed with an autosomal dominant hereditary neuropathy with symptoms including pes cavus, atrophy of the hand muscles, steppage gait, and sensory loss in all limbs. Nerve conduction studies reveal a pattern of demyelination. By convention, what would be the most correct classification for this condition?

A. Charcot-Marie-Tooth type 1 (CMT1)

B. Charcot-Marie-Tooth type 2 (CMT2)

C. Distal hereditary sensory neuropathy

D. Hereditary autonomic neuropathy

E. Hereditary sensory neuropathy

View Answer

15. Answer A. (MN-92) Hereditary neuropathies are classified as CMT (or hereditary motor sensory neuropathy) if motor and sensory system are both affected; as hereditary sensory/autonomic neuropathy (HSN or HSAN) if sensory and/or autonomic dysfunction prevail; and as distal hereditary motor neuropathy (dHMN) if motor deficit is predominant. These three disorders represent a continuum and are often collectively termed Charcot-Marie-Tooth and related disorders. CMT neuropathies are classified into two main subgroups: the demyelinating type CMT1 with reduced nerve conduction velocities (NCVs) and the axonal type CMT2 with primarily axonal loss characterized by normal NCV and decreased amplitude of motor (CMAP) and sensory nerve action potentials (SNAP). Further subdivision of CMT is based on the inheritance pattern and the molecular genetic defects. Inheritance in CMT can be autosomal dominant (AD), autosomal recessive (AR), or X-linked. By convention, AR demyelinating forms of CMT1 are referred to as CMT4, and AR axonal forms are also known as AR-CMT2. X-linked CMT is usually referred to as CMTX.

16. A 6-year-old girl presents with a progressive weakness and wasting distally in all four limbs and vocal cord paralysis. She has no sensory deficit. Which genetic testing is most likely to be positive?

A. Deletion/duplication in peripheral myelin protein 22 (PMP22)

B. Gap junction beta 1 (GJB1)

C. Heat shock protein family B member 8 (HSPB8)

D. Myelin protein zero (MPZ)

E. Transient receptor potential cation channel subfamily V member 4 (TRPV4)

View Answer

16. Answer E. (MN-92) TRPV4 has a phenotype with predominant motor involvement, vocal cord paralysis (hoarseness and stridor), and respiratory dysfunction. Other distinctive clinical features may include bone deformities such as scoliosis, short stature, and/or scapular winging. None of the other genes are usually associated with vocal cord paralysis.

17. Which is the most frequent form of Charcot-Marie-Tooth (CMT)?

A. CMT1A

B. CMT1B

C. CMT1X

D. CMT2A

E. Hereditary neuropathy with liability to pressure palsies (HNPP)

View Answer

17. Answer A. (MN-92) CMT1A accounts for about 60% of patients with genetic diagnosis and about half of all patients with CMT. CMT1X comprises approximately 10% to 20% of CMT cases and CMT1B accounts for about 7%. Patients with CMT2 are about 15% to 20% of all cases, and CMT2A is the most frequent form comprising roughly 20% of patients with CMT2. The prevalence of HNPP is about 3% of patients with genetic diagnosis.

18. Autonomic system involvement is frequently seen in:

A. Dejerine–Sottas neuropathy (DSN)

B. Distal hereditary motor neuropathy (dHMN)

C. Hereditary motor-sensory neuropathy (HMSN)

D. Hereditary neuropathy with liability to pressure palsies (HNPP)

E. Hereditary sensory autonomic neuropathy (HSAN)

View Answer

18. Answer E. (MN-92) HSAN is a group of severe disorders affecting peripheral sensory and autonomic neurons with considerable clinical and genetic heterogeneity. These patients tend to have more serious complications than HMSN due to the frequent occurrence of ulcers, amputations, and variably severe autonomic dysfunction. Motor involvement can be present, but generally, the sensory/autonomic features are prominent. In dHMN, the motor deficit is predominant. HNPP phenotype is characterized by recurrent episodic painless mononeuropathies typically at entrapment sites. DSN is currently used primarily to denote severe early-onset clinical phenotypes regardless of the inheritance pattern.

19. Which of the following antibodies is the most common etiology of autoimmune-mediated neuromuscular junction disease?

A. Acetylcholine receptor binding antibodies

B. Acetylcholine receptor blocking antibodies

C. Acetylcholine receptor modulating antibodies

D. Anti-LRP4 (low-density lipoprotein receptor-related protein 4) antibodies

E. Anti-MuSK (muscle-specific kinase) antibodies

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19. Answer A. (MN-93) In myasthenia gravis (MG), the most common disease of the neuromuscular junction, the majority of patients (80%) have antibodies that bind to the post-synaptic membrane and cause immune-mediated destruction of the receptor. Approximately 10% have AchR-blocking antibodies, and 1% have modulating antibodies. Antibodies against the MuSK protein on the muscle membrane are seen in approximately 10% of MG patients. Antibodies against LRP4, a post-synaptic protein involved in clustering of Ach receptors, is much less common.

20. Which of the following features of myasthenia gravis most likely signals impending respiratory failure?

A. Diplopia

B. Fatigue in proximal legs

C. Hypoventilation

D. Nasal speech

E. Ptosis

View Answer

20. Answer C. (MN-93) Hypoventilation and hypoxia are late manifestations of myasthenia gravis, either as a presentation or exacerbation. Other features of impending respiratory failure include serious bulbar dysfunction when accompanied by indications of respiratory distress as indicated in Table 12.20.1. The other answers typically present earlier in the course of either first presentation of myasthenia or an exacerbation. Ocular muscles are affected first in about 40% of patients and are ultimately involved in about 85%. Ptosis and diplopia are the symptoms that result. Other common symptoms affect facial or oropharyngeal muscles, resulting in dysarthria, dysphagia, and limitation of facial movements. Together, oropharyngeal and ocular weakness cause symptoms in virtually all patients with acquired MG. Limb and neck weakness is also common in conjunction with cranial weakness. Almost never are the limbs affected alone. MuSK myasthenia particularly involves ocular, facial, and bulbar muscles and has high risk of respiratory insufficiency. MuSK myasthenia can follow a rapidly progressive and more severe course.

TABLE 12.20.1 Signs of Impending Respiratory Failure in Myasthenia Gravis

Clinical features	Significant bulbar dysfunction Dysarthria, dysphagia Impaired gag reflex Tachypnea, dyspnea Use of accessory muscles Paradoxical breathing Count out loud in single exhale Poor cough Impaired secretion clearance
Laboratory signs	Pulmonary function tests: VC < 15-20 mL/kg (or VC < 1 L) NIF > −20 cm H₂O MEP < 40 cm H₂O Tidal volume <4-5 mL/kg Laboratory: Pco₂ ≥ 50 mm Hg^a
MEP, maximal expiratory pressure; NIF, negative inspiratory force; VC, vital capacity.
^aHypoxia is a late finding.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

21. A 48-year-old woman presents with new bilateral facial weakness and ptosis. Which of the following tests is the most sensitive for myasthenia gravis?

A. Anti-LRP4 autoantibodies

B. CT of the chest showing the presence of thymoma

C. Nerve conduction studies showing decremental response to repetitive nerve stimulation

D. Presence of AChR-binding antibodies

E. Single-fiber EMG showing increased jitter

View Answer

21. Answer E. (MN-93) Single-fiber EMG is >95% sensitive for diagnosis of myasthenia gravis; however, it is only ~70% specific. Repetitive nerve stimulation studies are often negative in persons with predominantly or exclusively extraocular involvement, and single-fiber EMG may be particularly useful in diagnosing these patients, especially if antibody testing is negative. Thymoma is present in ~10% of myasthenia gravis patients but is not sensitive for diagnosis. AChR-binding antibodies are present in about 80% of myasthenia gravis patients but can be non-specific without appropriate clinical context.

22. Which of the following is considered first-line treatment for myasthenia gravis with mild symptoms?

A. Acetylcholinesterase inhibitors

B. Bronchodilators

C. High-dose prednisone

D. Intravenous immunoglobulin

E. Mycophenolate mofetil

View Answer

22. Answer: A. (MN-93) For patients with mild symptoms, acetylcholinesterase inhibitors such as pyridostigmine are the first-line treatment. Low-dose prolonged course of prednisone may be used in this setting as well. High-dose corticosteroids are used in highly symptomatic exacerbations, and mycophenolate mofetil may be used as a long-term immunosuppressant regimen. Bronchodilators are not a specific treatment for myasthenia gravis. Intravenous immunoglobulin is indicated for moderate to severe exacerbations and may be part of a regimen of maintenance therapy for some patients. Subcutaneous immunoglobulin preparations may serve as a reasonable alternative to patients requiring long-term intravenous immunoglobulin for the management of myasthenia gravis. All treatments are individualized in myasthenia gravis, and several new monoclonal antibody therapies have become a part of precision-guided care (see Figure 12.22.1).

FIGURE 12.22.1 (Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.)

23. A 44-year-old man reports approximately 5 months of difficulty ascending stairs, in addition to neck weakness and proximal leg weakness. Laboratory studies show elevated creatine kinase and transaminitis. A careful inspection shows dry skin but no rashes. Muscle biopsy is performed, showing no necrosis and otherwise nonspecific features. Based on the Bohan and Peter criteria for Myositis, what would be this patient’s diagnosis?

A. Definite dermatomyositis

B. Definite polymyositis

C. Dermatomyositis definitely excluded

D. Possible polymyositis

E. Possible dermatomyositis

View Answer

23. Answer D. (MN-94) The classification and diagnosis of myositis originally developed by Bohan and Peter in 1975 remains widely used to this day (Table 12.23.1). Numerous additional classification systems have been proposed over the years to take into account clinical, pathologic, and serologic discoveries. Currently, there are five main subtypes of idiopathic inflammatory myopathies (IIMs) that are now widely recognized, including dermatomyositis, antisynthetase syndrome and overlap myositis, inclusion body myositis, polymyositis, and immune-mediated necrotizing myopathy. Subtypes of the IIMs can be distinguished based on clinical features, myositis-specific and myositis-associated antibodies, and histopathologic correlates. With proximal weakness and elevated muscle enzymes, this patient has two of the five Bohan and Peter criteria and would be diagnosed with possible polymyositis.

TABLE 12.23.1 Bohan and Peter Criteria for Myositis^a

Criterion	Description
Symmetric proximal weakness (over weeks to months)	Neck flexors, limb-girdle musculature
Consistent muscle biopsy findings	Necrosis, regeneration, phagocytosis, atrophy, mononuclear cell infiltrates
Elevated muscle enzymes	Creatine kinase, aldolase, transaminases, lactate dehydrogenase
Electromyographic evidence for myopathy	Muscle fiber irritability (positive sharp waves, fibrillations), short duration, small amplitude, polyphasic motor unit potentials, with spontaneous bizarre high-frequency discharges
Characteristic skin rash	Gottron sign, Gottron papules, heliotrope
^aDefinite polymyositis: four criteria; definite dermatomyositis: three or four criteria plus rash; possible polymyositis: two criteria; possible dermatomyositis: one criterion plus rash.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

24. Which of the following autoantibodies are associated with the dermatomyositis phenotype, which is characterized by minimal muscle involvement, presence of the classic rash, and an associated malignancy?

A. Anti-MDA5

B. Anti-Mi-2

C. Anti-NXP-2

D. Anti-SAE

E. Anti-TIF-1

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24. Answer E. (MN-94) Approximately 70% of patients with dermatomyositis (DM) will have DM-specific autoantibodies (Table 12.24.1). Anti-TIF-1 is associated with DM and high risk of malignancy. Anti-Mi-2 is associated with moderate muscle involvement and classic skin rash. Anti-NXP-2 is associated with moderate muscle involvement, presence of skin rash, as well as calcinosis and dysphagia and may be associated with malignancy. Anti-MDA5 is associated with minimal muscle involvement and associated with interstitial lung disease. Anti-SAE is associated with mild muscle involvement and classic skin rash.

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