The muscular dystrophies are diseases associated with abnormalities of the muscle membrane and are characterized by progressive loss of skeletal muscle function (Table 23-1) (Fig. 23-2).¹ Dysfunctions of cardiac and smooth muscle are less evident but contribute significantly to morbidity and mortality.

Myotonia is the delayed relaxation of skeletal muscle after voluntary contraction. Electromyography demonstrates repetitive
muscle fiber discharges that fluctuate. These abnormalities are caused by dysfunction of ion channels in the muscle membrane. There are two types of myotonic dystrophy caused by mutations in two distinct gene loci: Myotonic dystrophy type 1 and myotonic dystrophy type 2. The genetic alteration in type 1 is an unstable trinucleotide expansion (CTG) on chromosome 19q. Type 2 is caused by a quadnucleotide expansion (CCTG) on chromosome 3q. Both mutations produce RNA toxicity.

Myotonic dystrophy type 1 is the more common form and is subdivided by age of onset (Table 23-2). Type 1 is a multisystem disease that affects the musculoskeletal system, the heart, the respiratory system, central nervous system, and endocrine system.⁸ Muscle weakness begins distally and progresses to proximal muscles and muscle wasting occurs over time. Pulmonary function studies demonstrate a restrictive pattern, mild arterial hypoxemia, and diminished ventilatory responses to hypoxia and hypercapnia. Respiratory muscle weakness diminishes the effectiveness of cough and may lead to pneumonia. Aspiration of gastric contents may occur because of gastric atony and pharyngeal muscle dysfunction. Myotonia of the respiratory muscles can produce intense dyspnea.

Cardiac manifestations include atrioventricular (AV) conduction delay, atrial tachydysrhythmias, diastolic dysfunction, cardiomyopathy, and mitral valve prolapse. Sudden death may be secondary to third degree atrioventricular block or ventricular dysrhythmias. Echocardiography may reveal subclinical evidence of left ventricular systolic and diastolic function.⁹

Other clinical features include cataracts, premature balding, diabetes mellitus, thyroid dysfunction, adrenal insufficiency, and gonadal atrophy. Pregnancy often produces an exacerbation of myotonic dystrophy and congestive heart failure is more likely to occur during pregnancy. Cesarean section is often required because of uterine smooth muscle dysfunction. Infants of mothers with myotonic dystrophy may develop congenital myotonic dystrophy that features hypotonia, feeding difficulty, and respiratory failure.

Until specific molecular therapies are available, treatment is directed at symptom management, such as pacemaker implantation for cardiac dysrhythmias or surgery for cataracts or gallbladder dysfunction.

The familial periodic paralyses are a subgroup of diseases referred to as the hereditary skeletal muscle ion channelopathies. This group of diseases includes hyperkalemic and hypokalemic periodic paralysis, myotonia congenita, paramyotonia congenita, and the sodium channel myotonias. Alterations in the sodium, potassium, and calcium channels result in muscle membrane inexcitability and weakness.¹⁵

Myasthenia gravis (MG) is an autoimmune disease with antibodies directed against acetylcholine receptors or other proteins in the postsynaptic membrane of the neuromuscular junction (NMJ). Eighty-five percent of patients with MG have identifiable antiacetylcholine receptor antibodies. Seventy percent of MG patients without AChR (AChR-MG) antibodies have autoantibodies against other NMJ proteins such as muscle specific tyrosine kinase (MuSK, MuSK-MG). It is likely that seronegative MG patients have low antibody titer levels that are not measurable by current assay techniques. The autoantibodies damage the muscle membrane by activation of complement, lysis of the postsynaptic membrane, and loss of postsynaptic folds.¹⁷ The thymus may play a central role in the pathogenesis of MG as 90% of MG patients have histologic abnormalities such as thymoma, thymic hyperplasia, or thymic atrophy.

The clinical hallmark of MG is skeletal muscle weakness. The weakness is aggravated by repetitive muscle use and there are periods of exacerbation alternating with remission. Any skeletal muscle can be affected, although there is a predilection for muscles innervated by cranial nerves. Initial symptoms include diplopia, dysarthria, dysphagia, or limb muscle weakness. Myasthenic crises occur in 20% to 30% of MG patients and can be precipitated by poor control of MG, emotional stress, hyperthermia, or pulmonary infections. Myasthenic crisis is characterized by severe muscle weakness and respiratory failure. Cardiac manifestations of MG include focal myocarditis, atrial fibrillation, atrioventricular conduction delay, and left ventricular diastolic dysfunction.

Some pregnant patients have a remission during pregnancy while others (20% to 40%) have increased symptoms during gestation and postpartum respiratory failure can occur. Fifteen percent to twenty percent of neonates born to myasthenic mothers have transient myasthenia from passive transfer of acetylcholine receptor antibodies. Neonatal myasthenia begins 12 to 48 hours after birth and may persist for weeks. Babies from mothers with MuSK-MG have more severe neonatal myasthenia.

Disease classification is based on skeletal muscle groups affected as well as age of onset (Table 23-4). The Osserman staging system is based on the severity of the disease (Table 23-5).

No single test is definitive for the diagnosis of MG and the diagnosis is not always obvious. Serologic testing may detect anti-AChR or anti-MuSK antibodies. Single fiber electromyography is the most sensitive of the electrodiagnostic tests.¹⁸

Treatment includes the administration of cholinesterase inhibitors (pyridostigmine), corticosteroids, immunosuppressants, intravenous immunoglobulin (IVG), and plasmapheresis. Cholinesterase inhibitors increase the concentration of acetylcholine (ACh) at the postsynaptic membrane. Consistent control of MG with only pyridostigmine can, however, be quite challenging. Under-dosing will result in residual muscle weakness and over-dosing may produce a “cholinergic crisis” characterized by abdominal pain, salivation, bradycardia, and skeletal muscle weakness. Corticosteroids (prednisone) are nonspecific immunosuppressants used when pyridostigmine does not produce satisfactory control. Azathioprine is the most frequently prescribed
specific immunosuppressant for the treatment of MG. Other immunosuppressants under investigation include cyclosporine, tacrolimus, mycophenolate, cyclophosphamide, methotrexate, and rituximib. The administration of IVG and plasmapheresis are used when rapid treatment is required.¹⁹

The role of thymectomy for the treatment of MG remains controversial. Ten percent of MG patients have a thymoma and thymectomy is clearly indicated. Less invasive surgical techniques for thymectomy such as video-assisted thorascopic surgery (VATS) produce good results with a low incidence of perioperative complications.²⁰

The Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disease frequently associated with cancers and is categorized as a paraneoplastic syndrome.²⁴ Many tumors express onconeural antigens that resemble normal neural tissue components. Autoantibodies are produced that attack neural tissue. Patients with LEMS have autoantibodies directed against presynaptic voltage-gated calcium ion channels. This results in a decreased release of acetylcholine and subsequent muscle weakness. The muscle weakness often appears months to years before the diagnosis of the malignancy. Small cell lung cancer is most frequently associated with LEMS. The typical LEMS patient is a male older than 40 years of age with proximal muscle weakness (hip, shoulder) that affects gait and the ability to stand and climb stairs (Table 23-6). Autonomic dysfunction with dry mouth, constipation, erectile dysfunction, and reduced sweating often occurs. Paraneoplastic neurologic syndrome has also been reported with breast and ovarian cancers, lymphomas, testicular cancer, and neuroblastoma.

Treatment of the underlying neoplasm may improve the neurologic condition. The most effective drug for the treatment of LEMS associated muscle weakness is 3,4-diaminopyridine. 3,4-diaminopyridine prolongs the presynaptic action potential and increases the release of acetylcholine. Immunosuppression with corticosteroids and azathioprine may also be beneficial. Plasmapheresis and intravenous immunoglobulin may produce short-term improvement.²⁵

Guillain–Barré syndrome (GBS) is the acute form of a group of disorders classified as the inflammatory neuropathies. Other diseases in this group include acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy, Miller-Fisher syndrome, and chronic inflammatory demyelinating polyneuropathy (CIDP).

GBS is an autoimmune disease triggered by a viral or bacterial infection and is an example of molecular mimicry and cross-reactivity. The infectious agent produces a substance that causes an immune reaction. Unfortunately, that substance resembles a neural component of the host and autoantibodies develop that attack the host. Patients with GBS develop antibodies to gangliosides in the peripheral nerves.²⁶ Most patients with GBS have a history of a respiratory or gastrointestinal infection within 4 weeks of the onset of neurologic symptoms. Infections with Campylobacter jejuni, Haemophilus influenzae, Mycoplasma pneumoniae, Epstein-Barr virus, and cytomegalovirus are most frequently associated with GBS. There are sporadic case reports of GBS or a GBS-like syndrome presenting after surgical procedures.

GBS is characterized by onset of skeletal muscle weakness or paralysis of the legs. Paresthesias may precede the weakness. The paralysis progresses cephalad to include muscles of the trunk and arms with maximal weakness developing 2 to 4 weeks after the onset. A plateau phase usually develops before recovery begins. The most serious problem is ventilatory insufficiency and 25% of patients with GBS will require mechanical ventilation. Although 85% of GBS patients achieve a good recovery, 3% to 5% develop a chronic, recurrent neuropathy.

Autonomic nervous system dysfunction can produce wide fluctuations in cardiovascular parameters. In a manner similar to autonomic hyperreflexia, physical stimulation can precipitate hypertension, tachycardia, and cardiac dysrhythmias.

Plasma exchange and the administration of intravenous immunoglobulin have been shown to be effective for patients with GBS.²⁷

The features of multiple sclerosis (MS) are inflammation and demyelination in the brain and spinal cord. Although circulating T cells cannot normally penetrate the blood–brain barrier, an environmental stimulus (virus) may activate T cells. The activated T cells cross the blood–brain barrier and initiate an inflammatory and immunologic attack on myelin.³⁰,³¹ Demyelination interferes with neural transmission and causes CNS dysfunction. The ability of neural tissue to repair itself during the early phases of the disease explains the relapsing nature of MS. There is also evidence that damage is not restricted to white matter and that gray matter is also affected.

The symptoms of MS depend on the sites of demyelination. Brainstem involvement can produce nystagmus, diplopia, trigeminal neuralgia, autonomic dysfunction, and alterations in ventilation that lead to hypoxemia and respiratory failure. Lesions of the spinal cord produce weakness and paresthesias. The legs are affected more than the arms. Bowel retention and urinary incontinence are frequent complaints. The course of MS is characterized by exacerbations of symptoms at unpredictable intervals over a period of years. Patients are classified during the early phases as either relapsing–remitting (85%) or primary progressive MS. Many patients with relapsing–remitting MS develop neurodegeneration and are categorized as secondary progressive MS. Patients with primary progressive MS are devoid of acute episodes, but develop progressive neurodegeneration. Pregnancy is associated with improvement of symptoms, but relapse often occurs within the first three postpartum months.

Clinical criteria for the diagnosis of MS include onset between 10 and 50 years of age, signs and symptoms of CNS white matter disease, two or more attacks separated by a month or more, and involvement of two or more non-contiguous anatomic areas. Elevated levels of IgG and albumin in the cerebrospinal fluid are characteristic of MS. Magnetic resonance imaging (MRI) is a sensitive diagnostic tool for MS and provides direct evidence of the location of demyelinated plaques in the CNS.³²

Therapy for MS is directed at modulating the immunologic and inflammatory responses that damage the CNS. Current therapy for MS includes interferon preparations, glatiramer, mitoxantrone, and monoclonal antibodies. Interferon works by reducing T cell transit across the blood–brain barrier. Glatiramer is a mixture of polypeptides that mimic the structure of myelin and serve as a decoy for autoantibodies. Mitoxantrone is related to the antineoplastic drugs doxorubicin and may be cardiotoxic. Natalizumab prevents T cell migration but can produce a fatal leukoencephalopathy. The most recent therapeutic breakthrough in the treatment of MS has been the development of oral agents.³³ These include cladribine, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate. Corticosteroids are still used for acute relapses that do not respond to other medications.

Many patients with MS experience chronic pain, including central neuropathic pain, paresthesias, trigeminal neuralgia, and spasticity. Symptomatic therapy includes diazepam, dantrolene, and baclofen for spasticity. Painful dysesthesias, tonic seizures, and ataxia can be treated with carbamazepine. Nonspecific measures include the avoidance of excessive fatigue, emotional stress, and hyperthermia. Demyelinated fibers are extremely sensitive to increases in temperature and hyperthermia can block impulse conduction.

A seizure is a common manifestation of many types of CNS disease and is the external manifestation of epilepsy. A seizure results from the excessive discharge of large numbers of neurons that become depolarized in a synchronous fashion. Epilepsy (idiopathic seizures) begins in childhood. The sudden onset of seizures in an adult may indicate focal brain disease (tumor). The onset of seizures after 60 years of age can be a result of cerebrovascular disease, head injury, tumor, infection, or a metabolic disturbance.

Although there are many antiseizure drugs, 30% of epileptic patients are poorly controlled and sudden death may occur in adults with epilepsy since childhood (Table 23-7).³⁶,³⁷ The newer antiseizure drugs target ion channels, GABA receptors, amino acid receptors, and synaptic proteins.³⁸

The most frequently encountered types of seizures are:

Alzheimer disease is the major cause of dementia in the United States and there are over 5 million people in the United States with the disease. The incidence is 5% in persons over the age of 65 years and 30% over the age of 85 years. Alzheimer disease is characterized by cognitive impairment, poor decision making, language deterioration, gait disturbances, seizures, agitation, and psychosis. A positive diagnosis can, however, only be made at autopsy. Imaging studies show hippocampal atrophy (MRI) and glucose hypometabolism (PET). The deposition of amyloid β peptides appears to be central to the degeneration and death of neurons. Deposition of amyloid β peptides produces amyloid plaques and neurofibrillary tangles and activates the apoptotic cell death cascade. There is no specific therapy for Alzheimer disease. Initial symptomatic therapy is with cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and an NMDA receptor antagonist (memantine). Cholinesterase inhibitors improve the patient’s ability to perform daily living activities and may improve cognition. Side effects of cholinesterase inhibitors include nausea, emesis, bradycardia, syncope, and fatigue. Antidepressants, anticonvulsants, and antipsychotics are used for neuropsychiatric symptoms as necessary. A large number of experimental therapies are directed at disease modifying pathways with immunotherapy, secretase inhibitors, amyloid aggregators, chelation, and Tau aggregation inhibitors.⁴⁴

Parkinson disease (PD) is a degenerative CNS disease caused by a loss of dopaminergic cells in the basal ganglia of the brain. The characteristic pathologic feature is the presence of Lewy bodies in the neurons of the substantia nigra. Lewy bodies are aggregations of damaged proteins. The etiology of PD is an interaction of a genetic predisposition and unidentified environmental factors. Other than the well-described postencephalitic PD, there is little evidence that PD is caused by a virus.⁴⁸

The clinical effects of PD are caused by dopamine deficiency. The most characteristic features of PD are resting tremor, cogwheel rigidity of the extremities, bradykinesia, shuffling gait, stooped posture, and facial immobility. These features are secondary to diminished inhibition of the extrapyramidal motor system as a result of dopamine deficiency. Other clinical features include seborrhea, sialorrhea, orthostatic hypotension, bladder dysfunction, diaphragmatic spasm, oculogyric crisis, dementia, and mental depression.

Treatment is directed toward increasing dopamine levels in the brain, but preventing the adverse peripheral effects of dopamine. Levodopa is the single most effective drug for patients with PD. When administered orally, levodopa is converted to dopamine and causes side effects such as nausea, emesia, and hypotension. To avoid such side effects, levodopa is administered with carbidopa and entacopone. Carbidopa is a peripheral decarboxylase inhibitor and entacopone is a catechol-O-methyltransferase inhibitor that increases the bioavailability of levodopa. Other drugs that improve function are the monoamine oxidase-B inhibitors, selegiline and rasagiline. Dopamine receptor agonists such as bromocriptine, pramipexole, ropinirole, pergolide, and cabergoline can also be used for the treatment of PD. Pergolide and cabergoline are ergot-derived drugs that can cause cardiac valvular fibrosis and insufficiency. Implantation of deep-brain stimulators (DBS) may be quite effective for patients with advanced PD. The therapeutic regimen for patients with PD is complex and requires a skilled neurologist to individualize therapy.⁴⁹