Color Atlas of Neurology (Thieme 2004)

Myasthenic Syndromes

! Myasthenia Gravis (MG)

Pathogenesis. The exercise-induced weakness that typifies MG is due to impaired transmission at the neuromuscular junction, which is, in turn, due to an underlying molecular lesion affecting the nicotinic acetylcholine receptor (AChR) in the postsynaptic membrane of the muscle cell. Circulating IgG autoantibodies to this receptor impair its function, speed its breakdown, and induce complement-mediated damage to the muscle cell membrane. Recently the anti-MuSK (receptor tyrosine kinase) antibody has been detected in about half of patients who are seronegative for AChR antibodies. The thymus plays an important role in this autoimmune disorder (it is normally a site of maturation and removal of autoreactive T lymphocytes). MG is usually acquired late in life; there are also rare congenital and familial forms.

tor, such as pyridostigmine bromide; if the response is insufficient, corticosteroids or azathioprine can be added. Generalized MG is treated initially with AChE inhibitors and, if the response is insufficient, with corticosteroids, azathioprine, intravenous gammaglobulin, or plasmapheresis; once the patient’s condition has stabilized, thymectomy is performed. Further treatment depends on the degree of improvement achieved by these measures. The mortality of MG with optimal management is less than 1%. Most patients can lead a normal life but need lifelong immunosuppression. Specific measures are needed to manage respiratory crises, thymoma, and pregnancy in patients with MG, and for the treatment of neonatal, congenital, and hereditary forms of MG.

!Lambert–Eaton Myasthenic Syndrome (LEMS)

Symptoms and signs. MG is characterized by asymmetric weakness and fatigability of skeletal muscle that worsens on exertion and improves at rest. Weakness often appears first in the extraocular muscles and remains limited to them in some 15% of cases (ocular myasthenia), but progresses to other muscles in the rest (generalized myasthenia). The facial and pharyngeal muscles may be affected, resulting in a blank facial expression, dysarthria, difficulty in chewing and swallowing, poor muscular control of the head, and rhinorrhea. Respiratory weakness leads to impairment of coughing and an increased risk of aspiration. It may become difficult or impossible for the patient stand up, remain standing, or walk, and total disability may ensue. Myasthenia can be aggravated by certain medications (Table 72, p. 403), infections, emotional stress, electrolyte imbalances, hormonal changes, and bright light (eyes), and is often found in association with hyperthyroidism, thyroiditis, rheumatoid arthritis, and connective tissue disease. Myasthenic or cholinergic crises can be life-threatening (Table 73, p. 404). Diagnosis. The diagnosis is based on the characteristic history and clinical findings, supported by further tests that are listed in Table 74 (p. 404).

Treatment. Ocular MG is treated symptomatically with an acetylcholinesterase (AChE) inhibi-

LEMS is caused by autoantibodies directed mainly against voltage-gated calcium channels in the presynaptic terminal of the neuromuscular junction; diminished release of acetylcholine from the presynaptic terminal is the result. LEMS is often a paraneoplastic manifestation of bronchial carcinoma, sometimes appearing before the tumor becomes clinically evident. It is characterized by proximal (leg) weakness that improves transiently with exercise but worsens shortly afterward. There are also autonomic symptoms (dry mouth) and hyporeflexia. EMG reveals a diminished amplitude of the summated muscle action potential, which increases on high-frequency serial stimulation. The treatment is with 3,4-diaminopyridine (which increases acetylcholine release) and AChE inhibitors. Immune suppression and chemotherapy of the underlying malignancy can also improve LEMS.

Cervical muscle weakness

Proximal muscle weakness and atrophy

Ischemic lesion of muscle fiber

Perifascicular atrophy (DM; cross section of muscle fiber)

Lymphomonocytic infiltrate in muscle, vessel (PM, cross section of muscle fiber)

Lid edema

Facial erythema

Proximal muscle weakness

Telangiectasis,

Polymyositis (PM) hemorrhage (nailbed)

Erythema in joint region (extensor side)

Dermatomyositis (DM)

Distal muscle atrophy

Bleeding

an autosomal dominant trait (gene loci: 19q13.1, 17q11–24, 7q12.1, 5p, 3q13.1, 1q32). The creatine kinase level may be chronically elevated in susceptible individuals, who can be identified with an in vitro contracture test performed in specialized laboratories. Persons suffering from central core disease, multicore disease, and King–Denborough syndrome (dwarfism, skeletal anomalies, ptosis, high palate) are also at risk for MH. Treatment: dantrolene.

Malignant neuroleptic syndrome clinically resembles MH; unlike MH, however, it is usually of subacute onset (days to weeks), it is not hereditary, and it is triggered by psychotropic drugs (haloperidol, phenothiazines, lithium). Malignant neuroleptic syndrome can also be induced by abrupt withdrawal of dopaminergic agents in patients with Parkinson disease.

Toxic Neuromuscular Syndromes

The muscle fiber lesions regress if the responsible substance is eliminated in timely fashion (Table 75, p. 405).

Myopathy in Endocrine Disorders

Hyperthyroidism or hypothyroidism, hyperparathyroidism, Cushing syndrome, steroid myopathy, and acromegaly all cause proximal weakness, while Addison disease and primary hyperaldosteronism usually cause generalized weakness. Timely correction of the endocrine disorder or withdrawal of steroid drugs is usually followed by improvement.

Critical Illness Polyneuropathy (CIP)

and Critical Illness Myopathy (CIM)

Sepsis is the most common cause not only of encephalopathy (see p. 312) but also of CIP and CIM. CIP is an acute, reversible, mainly axonal polyneuropathy. It causes distal, symmetric weakness with prominent involvement of the muscles of respiration, resulting in prolonged ventilator dependence and delayed mobilization. CIM causes generalized weakness. The clinical differentiation of CIM and CIP is difficult and often requires muscle biopsy.

Paraneoplastic Syndromes

(Table 76, p. 406)

Distant neoplasms can affect not only the CNS (see p. 388) but also the PNS and skeletal muscle. Remarkably, paraneoplastic syndromes sometimes appear months or years before the underlying malignancy becomes clinically manifest. Paraneoplastic neuromuscular syndromes typically present with marked weakness of subacute onset (i.e., developing over several days or weeks).

A detailed description of diagnostic evaluation procedures can be found in the textbooks listed on p. 409. The goals of history-taking, physical examination, and additional testing (if necessary) are:

!Data collection (manifestations of disease)

!Localization of the lesion

!Provision of an etiological diagnosis

"Data Collection

The diagnostic process begins with the history and physical examination. The history provides information about the patient’s experience of illness, the temporal course of symptom development, and potentially relevant familial, social, occupational, and hereditary factors. An inaccurate or incomplete history is a frequent cause of misdiagnosis.

History. The physician engages the patient in a structured conversation about the manifestations of the illness. The physician must remember that the patient is the “expert” in this situation, as the patient alone knows what is troubling him (though perhaps helpful information can also be obtained from a close relative or friend). The physician aims to obtain accurate information on the nature, location, duration, and intensity of the symptoms by listening patiently and asking directed questions in an atmosphere of openness and trust. Questionnaires, computer programs, and ancillary personnel cannot be used for primary his- tory-taking, as they do not enable the construction of a trusting physician–patient relationship (though they may provide useful additional information at a later stage). Some important elements of the case history are as follows.

!Nature of symptoms. The physician must ascertain, by detailed questioning if necessary, that he understands the patient’s complaints in the same sense that the patient means to convey. “Blurred vision” may mean diplopia, “dizziness” may mean gait ataxia, “headache” may mean hemicrania, “numbness” may mean paresthesia—but patients may use all of these terms with other meanings as well.

!Severity of symptoms. Quality and intensity of symptoms, activities with which they interfere.

!Onset of symptoms. When, where, and over what interval of time did the symptoms arise?

!Time course of symptoms. How did they develop? Are they constant or variable? Are there any exacerbating or alleviating factors?

!Accompanying symptoms, if present.

!Past history of similar symptoms.

!Previous illnesses and their outcome.

!Social, occupational, and family history.

!Medications, smoking, alcohol abuse, substance abuse, toxic exposures.

!Previous diagnostic studies and treatment.

!Information from third parties may be needed for patients with aphasia, confusion, demen-

tia, or impairment of consciousness.

Physical examination. The general and neurological physical examination may yield important clues to the disease process, but only if the examiner has the requisite knowledge of the underlying principles of (neuro-)anatomy, (neuro-)physiology, and (neuro-)pathology. The examination is guided by the case history, i.e., the patient’s complaints and general physical condition determine what the examiner looks for in the examination. The unselective, “shotgun” application of every possible technique of neurological examination in every patient is not only a waste of time and money; it generally only creates confusion rather than clarifying the search for the diagnosis. The neurological examination of small children, patients with personality changes or mental illness, and unconscious patients poses special challenges.

Important elements of the neurological examination include:

!Inspection. Dress, appearance, posture, movements, speech, gestures, facial expression.

!Mental Status. Orientation (to person, place, and time), attention, concentration, memory, thought processes, language function, level of consciousness.

!Cranial nerves. Olfaction, pupils, visual fields, eyegrounds, eye movements, facial movement, facial sensation, hearing, tongue movements, swallowing, speaking, reflexes.

!Motor function. Muscular atrophy/hypertrophy, spontaneous movements, coordination, paresis, tremor, dystonia, muscle tone.

!Reflexes (p. 40).

!Sensory function. The findings of sensory testing are heavily influenced by the patient’s “sensitivity” and ability to cooperate. Vague sensory abnormalities without other neurological deficits are difficult to classify; their interpretation requires a good knowledge of the underlying neuroanatomy (pp. 32ff, 106f).

!Posture, station, and gait. The observation and testing of posture, station, and gait provides important information about a possible motor deficit (p. 42 ff).

!Autonomic function. The patient is questioned about bladder function, bowel movement/control, sexual function, blood pressure, cardiac function, and sweating, and is examined as needed.

"Localization of the Lesion

The findings of the history and physical examination findings are then related to dysfunction of a particular neuroanatomical structure(s) (p. 2 ff) or neurophysiological process (p. 40 ff); the site of the patient’s problem is thus localized (topical diagnosis).

" Provision of an Etiological Diagnosis

Once the site of the problem is localized, it must be determined whether it is due to a structural lesion (e. g., hemorrhage, nerve compression, or infection) or a functional disturbance (e. g.,

epileptic seizure, migraine, or Parkinson disease). The line between structural and functional pathology is not perfectly defined, as there is constant interaction between these two levels; at the same time, considerations of etiology and pathogenesis also influence data interpretation. The diagnostic process ideally ends in the diagnosis of a specific disease entity (nosological diagnosis).

Additional Diagnostic Studies

The clinical diagnosis may be considered firmly established by the history and physical examination alone in many cases, e. g., migraine or Parkinson disease. Additional diagnostic studies are merely confirmatory and are generally not needed unless doubt arises as to the diagnosis, e. g., if an epileptic seizure or new type of headache should appear.

Additional studies are needed, however, if there is no other way to decide among several diagnostic possibilities remaining after thorough his- tory-taking and physical examination. The number and type of studies needed differ from case to case. Studies that are costly or fraught with nonnegligible risk should never be ordered except to answer a clearly stated diagnostic question. The potential benefits of a proposed study must always be weighed against its risks and cost.

" Laboratory Tests

Table 77, p. 407