Leave a comment

199 PSYCHIATRIC MEDICATIONS

199 PSYCHIATRIC MEDICATIONS
Harrison’s Manual of Medicine

199

PSYCHIATRIC MEDICATIONS

General Principles of Use

Antidepressants
Anxiolytics
Antipsychotic Medications
Mood-Stabilizing Agents
Bibliography

Four major classes of psychiatric medications are commonly used in adults: (1) antidepressants, (2) anxiolytics, (3) antipsychotics, and (4) mood stabilizing agents. Nonpsychiatric physicians should become familiar with one or two drugs in each of the first three classes so that the indications, dose range, efficacy, potential side effects, and interactions with other medications are well known.
GENERAL PRINCIPLES OF USE

1.
Most treatment failures are due to undermedication and impatience. For a proper medication trial to take place, an effective dose must be taken for an adequate amount of time. For antidepressants, antipsychotics, and mood stabilizers, full effects may take weeks or months to occur.

2.
History of a positive response to a medication usually indicates that a response to the same drug will occur again. A family history of a positive response to a specific medication is also useful.

3.
Pts who fail to respond to one drug will often respond to another in the same class; one should attempt another trial with a drug that has a different mechanism of action or a different chemical structure. Treatment failures should be referred to a psychiatrist, as should all pts with psychotic symptoms or who require mood stabilizers.

4.
Avoid polypharmacy; a pt who is not responding to standard monotherapy requires referral to a psychiatrist.

5.
Pharmacokinetics may be altered in the elderly, with smaller volumes of distribution, reduced renal and hepatic clearance, longer biologic half-lives, and greater potential for CNS toxicity. The rule with elderly pts is to “start low and go slow.”

6.
Never stop treatment abruptly; especially true for antidepressants and anxiolytics. In general, medications should be slowly tapered and discontinued over 2–4 weeks.

7.
Review possible side effects each time a drug is prescribed; educate pts and family members about side effects and need for patience in awaiting a response.
Antidepressants
Useful to group according to known actions on CNS monoaminergic systems (Table 199-1). The selective serotonin reuptake inhibitors (SSRIs) have predominant effects on serotonergic neurotransmission, also reflected in side effect profile. The TCAs, or tricyclic antidepressants (ADs), affect noradrenergic and, to a lesser extent, serotonergic neurotransmission but also have anticholinergic and antihistaminic effects. Venlafaxine and mirtazapine have relatively “pure” noradrenergic and serotonergic effects. Bupropion has dopamine reuptake inhibitor properties. Trazodone and nefazodone have mixed effects on serotonin receptors and on other neurotransmitter systems. The MAOIs inhibit monoamine oxidase, the primary enzyme responsible for the degradation of monoamines in the synaptic cleft.

Table 199-1 Antidepressants

ADs are effective against major depression, particularly when neurovegetative symptoms and signs are present. In very severe depression with many endogenous features, TCAs or MAOIs are more efficacious than SSRIs. ADs are also useful in treatment of panic disorder, posttraumatic stress disorder, chronic pain syndromes, and generalized anxiety disorder. The SSRIs and the TCA clomipramine successfully treat obsessive-compulsive disorder.
All ADs require at least 2 weeks at a therapeutic dose before clinical improvement is observed. All ADs also have the potential to trigger a manic episode or rapid cycling when given to a pt with bipolar disorder. The MAOIs must not be prescribed concurrently with other ADs or with narcotics, as potentially fatal reactions may occur. “Withdrawal syndromes” usually consisting of malaise can occur when ADs are stopped abruptly.
ANXIOLYTICS
Antianxiety agents include the benzodiazepines and the nonbenzodiazepine buspirone.
Benzodiazepines bind to stereospecific sites on the g-aminobutyric acid receptor and are cross-tolerant with alcohol and with barbiturates. Four clinical properties: (1) sedative, (2) anxiolytic, (3) skeletal muscle relaxant, and (4) antiepileptic. Individual drugs differ in terms of potency, onset of action, duration of action (related to half-life and presence of active metabolites), and metabolism (Table 199-2). Benzodiazepines have additive effects with alcohol; like alcohol, they can produce tolerance and physiologic dependence, with serious withdrawal syndromes (tremors, seizures, delirium, and autonomic hyperactivity) if discontinued too quickly, especially for those with short half- lives.

Table 199-2 Anxiolytics

Buspirone is an anxiolytic that is nonsedating, is not cross-tolerant with alcohol, and does not induce tolerance or dependence. It acts via serotonergic pathways and requires at least 2 weeks at therapeutic doses to achieve full effects.
ANTIPSYCHOTIC MEDICATIONS
These include the typical (or conventional) neuroleptics, which act by blocking dopamine D2 receptors, and the atypical (or novel) neuroleptics, which act on dopamine, serotonin, and other neuroreceptor systems. Some antipsychotic effect may occur within hours or days of initiating treatment, but full effects usually require 6 weeks to several months of daily, therapeutic dosing.
CONVENTIONAL ANTIPSYCHOTICS   Useful to group into high-, mid-, and low-potency neuroleptics (Table 199-3). High-potency neuroleptics are least sedating, have almost no anticholinergic side effects, and have a strong tendency to induce extrapyramidal side effects (EPSEs) secondary to dopamine receptor blockade. The EPSEs occur within several hours to several weeks of beginning treatment and include acute dystonias, akathisia, and pseudo-parkinsonism. They are treated by judicious dose reduction and by use of anticholinergic and dopamine agonist medications. Low-potency neuroleptics are very sedating, may cause orthostasis, are anticholinergic, and therefore tend not to induce EPSEs. Mid-potency agents are best tolerated by the average pt.

Table 199-3 Antipsychotic Agents

10–20% of pts treated with conventional antipsychotic agents for >1 year develop tardive dyskinesia (probably due to dopamine receptor supersensitivity), an abnormal involuntary movement disorder most often observed in the face and distal extremities. Treatment includes gradual withdrawal of the neuroleptic, with possible switch to a novel neuroleptic; anticholinergic agents can worsen the disorder.
1–2% of pts exposed to neuroleptics develop neuroleptic malignant syndrome (NMS), a life-threatening complication with a mortality rate as high as 25%; hyperpyrexia, autonomic hyperactivity, muscle rigidity, obtundation, and agitation are characteristic, associated with increased WBC, increased CPK, and myoglobinuria. Treatment involves immediate discontinuation of neuroleptics, supportive care, and use of dantrolene and bromocriptine.
NOVEL ANTIPSYCHOTICS   A new class of agents that has become the first line of treatment (Table 199-3); efficacious in treatment-resistant pts, tend not to induce EPSEs or tardive dyskinesia, and appear to have uniquely beneficial properties on negative symptoms and cognitive dysfunction. Main problem is side effect of weight gain (most prominent in clozapine and in olanzapine; can induce onset of diabetes mellitus).
MOOD-STABILIZING AGENTS
Three mood stabilizers in common use: lithium, carbamazepine, and valproic acid or divalproex sodium. Three additional mood stabilizers being increasingly used: gabapentin, lamotrigine, topiramate (Table 199-4). Lithium is the “gold standard” and the best studied, and along with carbamazepine and valproic acid, is used for treatment of acute manic episodes; 1–2 weeks to reach full effect. As prophylaxis, the mood stabilizers reduce frequency and severity of both manic and depressed episodes in cyclical mood disorders. Believed to work at various sites of gaba-ergic and glutamenergic neurotransmission and second- messenger signal transduction systems in the CNS. In refractory bipolar disorder, combinations of mood stabilizers are often beneficial.

Table 199-4 Mood-stabilizing Agents

Bibliography

For a more detailed discussion, see Reus VI: Mental Disorders, Chap. 385, p. 2542, in HPIM-15.

Leave a comment

198 APPROACH TO THE PATIENT WITH PSYCHIATRIC SYMPTOMS

198 APPROACH TO THE PATIENT WITH PSYCHIATRIC SYMPTOMS
Harrison’s Manual of Medicine

198

APPROACH TO THE PATIENT WITH PSYCHIATRIC SYMPTOMS

Major Psychiatric Disorders (Axis I Diagnoses)

Mood Disorders (Major Affective Disorders)

Schizophrenia and Other Psychotic Disorders

Anxiety Disorders
Personality Disorders (Axis Ii Diagnoses)

Cluster A Personality Disorders

Cluster B Personality Disorders

Cluster C Personality Disorders
Bibliography

Disorders of mood, thinking and behavior may be due to a primary psychiatric diagnosis (DSM-IV* Axis I major psychiatric disorders) or a personality disorder (DSM-IV Axis II disorders) or may be secondary to metabolic abnormalities, drug toxicities, focal cerebral lesions, seizure disorders, or degenerative neurologic disease. Any pt presenting with new onset of psychiatric symptoms must be evaluated for underlying psychoactive substance abuse and/ or medical or neurologic illness. Specific psychiatric medications are discussed in Chap. 199. The DSM-IV-PC (Primary Care) Manual provides a synopsis of mental disorders commonly seen in medical practice.
MAJOR PSYCHIATRIC DISORDERS (AXIS I DIAGNOSES)
Mood Disorders (Major Affective Disorders)
MAJOR DEPRESSION   Clinical Features   Affects 15% of the general population at some point in life and extracts high disability and societal cost. Diagnosis is made when a depressed/irritable mood or a lack of normal interest/ pleasure exists for at least 2 weeks, in combination with four or more of the following symptoms: (1) change in appetite plus change in weight; (2) insomnia or hypersomnia; (3) fatigue or loss of energy; (4) motor agitation or retardation; (5) feelings of worthlessness, self-reproach, or guilt; (6) decreased ability to concentrate and make decisions; (7) recurrent thoughts of death or suicide. A small number of pts with major depression will have psychotic symptoms— hallucinations and delusions—with their depressed mood; many present with a “masked depression,” unable to describe their psychological distress but with multiple diffuse somatic complaints.
Onset of a first depressive episode is typically in the thirties or forties, although major depression is found in children and adolescents as well as geriatric pts. Untreated episodes generally resolve spontaneously in 5–9 months; however, a sizeable number of pts suffer from chronic, unremitting depression or from partial treatment response. Half of all pts experiencing a first depressive episode will go on to a recurrent course, with a second episode occurring within 2 years. Untreated or partially treated episodes put the pt at risk for future problems with mood disorder. A family history of mood disorder is common and tends to predict a recurrent course. Major depression can also be the initial presentation of bipolar disorder (manic depressive illness).
Suicide   Most suicides occur in pts with a mood disorder, and many pts seek contact with a physician prior to their suicide attempt. Physicians must always inquire about suicide when evaluating a pt with depression. Features that place a pt at high risk for suicidal behavior include: (1) a formulated plan and a method, as well as an intent; (2) prior attempts; (3) concomitant alcohol or other psychoactive substance use; (4) psychotic symptoms; (5) older age; (6) male gender; (7) Caucasian; (8) social isolation; (9) serious medical illness; (10) recent loss and/or profound hopelessness.

TREATMENT
Pts with suicidal ideation require treatment by a psychiatrist and may require hospitalization. Most other pts with an uncomplicated unipolar major depression (a major depression that is not part of a cyclical mood disorder, such as a bipolar disorder) can be successfully treated by a nonpsychiatric physician. Vigorous intervention and successful treatment appear to decrease the risk of future relapse. Pts who do not respond fully to standard treatment should be referred to a psychiatrist.
Antidepressant medication is the mainstay of treatment; symptoms are ameliorated after 2–6 weeks at a therapeutic dose. Antidepressants should be continued for 9–12 months, then tapered slowly. Pts must be monitored carefully after termination of treatment since relapse is common. The combination of pharmacotherapy with psychotherapy [usually cognitive-behavioral therapy (CBT) or interpersonal therapy (IPT)] produces better and longer-lasting results than drug therapy alone. Electroconvulsive therapy is generally reserved for pts with life-threatening depression unresponsive to medication or for pts in whom the use of antidepressants is medically contraindicated.

BIPOLAR DISORDER (MANIC DEPRESSIVE ILLNESS)   Clinical Features   A cyclical mood disorder in which episodes of major depression are interspersed with episodes of mania or hypomania; 1–2% of the population is affected. Most pts initially present with a manic episode in adolescence or young adulthood, but 20% present with a major depression. Antidepressant therapy is usually contraindicated in pts with a cyclical mood disorder because it may provoke a manic episode or make the cycles between mania and depression more frequent and more intense (“rapid cycling”). Pts with a major depressive episode and a prior history of “highs” (mania or hypomania—which can be pleasant/euphoric or irritable/impulsive) and/or a family history of bipolar disorder should not be treated with antidepressants but must be referred promptly to a psychiatrist.
With mania, an elevated, expansive mood, irritability, angry outbursts, and impulsivity are characteristic. Specific symptoms include: (1) increased motor activity and restlessness; (2) unusual talkativeness; (3) flight of ideas and racing thoughts; (4) inflated self-esteem that can become delusional; (5) decreased need for sleep (often the first feature of an incipient manic episode); (6) decreased appetite; (7) distractability; (8) excessive involvement in risky activities (buying sprees, sexual indiscretions). Pts with full-blown mania can become psychotic. Hypomania is characterized by attenuated manic symptoms and is greatly underdiagnosed, especially in nonpsychiatric settings. “Mixed episodes,” where both depressive and manic or hypomanic symptoms co-exist simultaneously, are also underrecognized and misdiagnosed.
Untreated, a manic or depressive episode typically lasts for 1–3 months, with cycles of 1–2 episodes per year. Risk for manic episodes increases in the spring and fall. Variants of bipolar disorder include rapid and ultrarapid cycling (manic and depressed episodes occurring at cycles of weeks, days, or hours). In many pts, especially females, antidepressants trigger rapid cycling and worsen the course of illness. Pts with bipolar disorder are at risk for psychoactive substance use, especially alcohol abuse, and for medical consequences of risky sexual behavior (STDs).
Bipolar disorder has a strong genetic component. Pts with bipolar disorder are vulnerable to sleep deprivation, to changes in the photoperiod, and to the effects of jet lag.

TREATMENT
Bipolar disorder is a serious, chronic illness that requires lifelong monitoring by a psychiatrist. Acutely manic pts often require hospitalization to reduce environmental stimulation and to protect themselves and others from the consequences of their reckless behavior. Mood stabilizers (lithium, carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate) are effective treatment and are used for the resolution of acute episodes and for prophylaxis of future episodes. Antipsychotic medication, benzodiazepines, and antidepressants such as buproprion may be part of the treatment regimen. As in unipolar depression, rapid therapeutic intervention may decrease the risk of future relapse.

Schizophrenia and Other Psychotic Disorders
SCHIZOPHRENIA   Clinical Features   Occurs in 1% of the population worldwide; 30–40% of the homeless are affected. Characterized by a waxing and waning vulnerability to psychosis, i.e., an impaired ability to monitor reality, resulting in altered mood, thinking, language, perceptions, behavior, and interpersonal interactions. Pts usually present between late adolescence and the third decade, often after an insidious premorbid course of subtle psychosocial difficulties. Core psychotic features last ³6 months and include: (1) delusions, which can be paranoid, jealous, somatic, grandiose, religious, nihilistic, or simply bizarre; (2) hallucinations, often auditory hallucinations of a voice or voices maintaining a running commentary; (3) disorders of language and thinking: incoherence, loosening of associations, tangentiality, illogical thinking; (4) inappropriate affect and bizarre, catatonic, or grossly disorganized behavior.
Many pts stabilize after the first 5 years of illness. 30–40% show a deteriorating course, but at least 25% do well, especially with early intervention. Females tend to have a later age of onset and a more benign course than males. Comorbid substance abuse is common, especially of nicotine, alcohol, and stimulants.

TREATMENT
Hospitalization is required for acutely psychotic pts, especially those with violent command hallucinations, who may be dangerous to themselves or others. Conventional antipsychotic medications are effective against hallucinations, agitation, and thought disorder (the so-called positive symptoms) in 60% of pts but are often less useful for apathy, blunted affect, social isolation, and anhedonia (negative symptoms). The novel antipsychotic medications—clozapine, risperidone, olanzapine, quetiapine, and others—have become the mainstay of treatment as they are helpful in pts unresponsive to conventional neuroleptics and may also be useful for negative and cognitive symptoms. Long-acting injectable forms of haloperidol and fluphenazine are ideal for noncompliant pts. Psychosocial intervention, rehabilitation, and family support are also essential.

OTHER PSYCHOTIC DISORDERS   These include schizoaffective disorder (where symptoms of chronic psychosis are interspersed with major mood episodes) and delusional disorders (in which a fixed, unshakable delusional belief is held in the absence of the other stigmata of schizophrenia). Pts with somatic delusions can be especially difficult to diagnose; they may become violent towards the physician if they feel misunderstood or thwarted and they almost always resist referral to a psychiatrist.
Anxiety Disorders
Characterized by severe, persistent anxiety or sense of dread in the absence of psychosis or a severe change in mood. Most prevalent psychiatric illness seen in the community; present in 15–20% of medical clinic patients.
PANIC DISORDER   Occurs in 1–2% of the population; female:male ratio of 2:1. Familial aggregation may occur. Onset in second or third decade. Initial presentation is almost always to a nonpsychiatric physician, frequently in the ER, as a possible heart attack or serious respiratory problem. The disorder is often initially unrecognized or misdiagnosed. Prompt diagnosis and treatment can greatly reduce morbidity.
Clinical Features   Characterized by panic attacks, which are sudden, unexpected, overwhelming paroxysms of terror and apprehension with multiple associated somatic symptoms. Attacks usually last 10–20 min, then slowly resolve spontaneously. Diagnostic criteria for panic disorder require four or more panic attacks within 4 weeks occurring in nonthreatening or nonexertional settings, and attacks must be accompanied by at least four of the following: dyspnea, palpitations, chest pain or discomfort, choking/smothering feelings, dizziness/vertigo/unsteady feelings, feelings of unreality, paresthesia, hot and cold flashes, sweating, faintness, trembling, and fear of dying, going crazy, or doing something uncontrolled during an attack. Panic disorder is often associated with a concomitant major depression.
When the disorder goes unrecognized and untreated, pts often experience significant morbidity: they become afraid of leaving home and may develop anticipatory anxiety, agoraphobia, and other spreading phobias; many turn to self-medication with alcohol or benzodiazepines.
Panic disorder must be differentiated from cardiovascular and respiratory disorders. Conditions that may mimic or worsen panic attacks include hyper- and hypothyroidism, pheochromocytoma, complex partial seizures, hypoglycemia, drug ingestions (amphetamines, cocaine, caffeine, sympathomimetic nasal decongestants), and drug withdrawal (alcohol, barbiturates, opiates, minor tranquilizers).

TREATMENT
Cognitive-behavioral psychotherapy (identifying and aborting panic attacks through relaxation and breathing techniques)—either alone or combined with medication—is highly effective. Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors all treat the disorder and prevent spontaneous attacks. Clonazepam, lorazepam, or other benzodiazepines may be used in the short term while waiting for antidepressants to take effect (2–3 weeks).

GENERALIZED ANXIETY DISORDER (GAD)   Characterized by persistent, chronic anxiety but without the specific symptoms of phobic, panic, or obsessive-compulsive disorders; occurs in 2–3% of the population.
Clinical Features   Pts experience persistent motor hyperactivity (shakiness, trembling, restlessness, easy startle), autonomic hyperactivity, apprehensive expectation (anxiety, fear, rumination, anticipation of misfortune, etc.), and vigilance (distractability, poor concentration, insomnia, impatience, and irritability). These symptoms are chronic and pervasive, rather than situational. Secondary depression is common.

TREATMENT
Benzodiazepines are the initial agents of choice when generalized anxiety is severe and acute enough to warrant drug therapy. A trial of an SSRI antidepressant should then be started as many pts will experience significant relief with this class of medications. Physicians must be alert to psychological and physical dependence on benzodiazepines. A subgroup of pts respond to buspirone, a nonbenzodiazepine anxiolytic. Psychotherapy and relaxation training can be useful.

OBSESSIVE-COMPULSIVE DISORDER (OCD)   A severe disorder present in 4–6% of the population and characterized by recurrent obsessions (persistent intrusive thoughts) and compulsions (repetitive behaviors) that the pt experiences as involuntary, senseless, or repugnant. Pts are often ashamed of their symptoms and only seek help after they have become debilitated.
Clinical Features   Common obsessions include thoughts of violence (such as killing a loved one), obsessive slowness for fear of making a mistake, fears of germs or contamination, and excessive doubt or uncertainty. Examples of compulsions include repeated checking to be assured that something was done properly, hand washing, extreme neatness and ordering behavior, and counting rituals, such as numbering one’s steps while walking.
Onset is usually in adolescence, with 65% of cases manifest before age 25. It is more common in males and in first-born children. In families of OCD patients, an increased incidence of both OCD and Tourette’s syndrome is found. The course of OCD is usually episodic with periods of incomplete remission. Pts with severe disease may become completely housebound. Major depression, substance abuse, and social impairment are common.

TREATMENT
Clomipramine and the SSRIs are highly effective. A combination of drug therapy and CBT is most effective for the majority of pts. Education and referral to a national support organization is also useful.

POSTTRAUMATIC STRESS DISORDER (PTSD)   Occurs in a subgroup of individuals exposed to a severe life-threatening trauma. Predisposing factors include a prior history of traumatization and/or a diathesis toward anxiety responses. Early psychological intervention following a traumatic event may reduce the risk for chronic PTSD.
Clinical Features   Three core sets of symptoms: (1) reexperiencing, where the pt unwillingly reexperiences the trauma through recurrent intrusive recollections, recurrent dreams, or by suddenly feeling as if the traumatic event is recurring; (2) avoidance and numbing, where the pt experiences reduced responsiveness to, and involvement with, the external world, a sense of a foreshortened future, and avoidance of activities that arouse recollection of the traumatic event; (3) arousal, characterized by hypervigilance, hyperalertness, an exaggerated startle response, sleep disturbance, guilt about having survived when others have not or about behavior required for survival, memory impairment or trouble concentrating, and intensification of symptoms by exposure to events that symbolize or resemble the traumatic event. Comorbid substance abuse and other mood and anxiety disorders are common. This disorder is extremely debilitating, particularly as it becomes chronic and affects psychosocial functioning. Most pts require referral to a psychiatrist for ongoing care.

TREATMENT
Medications used with varying success include a combination of an SSRI and trazodone, 50–200 mg qhs for sleep; tricyclic antidepressants; and mood stabilizers. Group psychotherapy (with other trauma survivors), alone or with individual psychotherapy, is useful.

PHOBIC DISORDERS   Clinical Features   Recurring, irrational fears of specific objects, activities, or situations, with subsequent avoidance behavior of the phobic stimulus. Diagnosis is made only when the avoidance behavior is a significant source of distress or interferes with social or occupational functioning.
1.   Agoraphobia: Fear of being in public places. May occur in absence of panic disorder, but is almost invariably preceded by that condition.
2.   Social phobia: Persistent irrational fear of, and need to avoid, any situation where there is risk of scrutiny by others, with potential for embarassment or humiliation. Common examples include excessive fear of public speaking and excessive fear of social engagements.
3.   Simple phobias: Persistent irrational fears and avoidance of specific objects. Common examples include fear of heights (acrophobia), closed spaces (claustrophobia), and animals.

TREATMENT
Agoraphobia is treated as for panic disorder. SSRIs are very helpful in treating social phobias. Social and simple phobias respond well to CBT and relaxation techniques and to systematic desensitization and exposure treatment.

SOMATOFORM DISORDERS   Clinical Features   Pts with multiple somatic complaints that cannot be explained by a known medical condition or by the effects of substances; seen commonly in primary care practice (prevalence of 5%). In somatization disorder, the pt presents with multiple physical complaints referable to different organ systems. Onset is before age 30, and the disorder is persistent; pts with somatization disorder can be impulsive and demanding. In conversion disorder, the symptoms involve voluntary motor or sensory function. In hypochondriasis, the pt believes there is a serious medical illness, despite reassurance and appropriate medical evaluation. As with somatization disorder, these pts have a history of poor relationships with physicians due to their sense that they have not received adequate evaluation. Hypochondriasis can be disabling and show a waxing and waning course. In factitious illnesses, the pt consciously and voluntarily produces physical symptoms; the sick role is gratifying. Munchausen’s syndrome refers to individuals with dramatic, chronic, or severe factitious illness. A variety of signs, symptoms, and diseases have been simulated in factitious illnesses; most common are chronic diarrhea, fever of unknown origin, intestinal bleeding, hematuria, seizures, hypoglycemia. In malingering, the fabrication of illness derives from a desire for an external gain (narcotics, disability).

TREATMENT
Pts with somatoform disorders are usually subjected to multiple diagnostic tests and exploratory surgeries in an attempt to find their “real” illness. This approach is doomed to failure. Successful treatment is achieved through behavior modification, in which access to the physician is adjusted to provide a consistent, sustained, and predictable level of support that is not contingent on the pt’s level of presenting symptoms or distress. Visits are brief, supportive, and structured and are not associated with a need for diagnostic or treatment action. Pts often benefit from antidepressant treatment. Consultation with a psychiatrist is essential.

PERSONALITY DISORDERS (AXIS II DIAGNOSES)
Defined as an inappropriate, stereotyped, maladaptive use of a certain set of psychological characteristics; affects 5–15% of the general population. The pattern of behavior is enduring and affects the person’s relationships and ability to function satisfactorily in life.
Comorbid Axis I diagnosis is common, as is a psychoactive substance use disorder. In medical and surgical settings, pts with personality disorders often become engaged in hostile, manipulative, or unproductive relationships with their physicians. Long-term psychotherapy is beneficial for pts who are motivated to change. Antidepressants and antipsychotic medications can be helpful, particularly for episodes of decompensation, but should be prescribed in consultation with a psychiatrist as misdiagnosis is common.
DSM-IV describes three major categories of personality disorders; pts usually present with a combination of features.
Cluster A Personality Disorders
Affected pts are often characterized as “wild” or “mad.” The paranoid personality is suspicious, hypersensitive, guarded, hostile, and can occasionally become threatening or dangerous. The schizoid personality is interpersonally isolated, cold, and indifferent, while the schizotypal personality is eccentric and superstitious, with magical thinking and unusual beliefs resembling schizophrenia.
Cluster B Personality Disorders
Patients with these disorders are often “wild” or “bad.” The borderline personality is impulsive and manipulative, with unpredictable and fluctuating intense moods and unstable relationships, a fear of abandonment, and occasional rageful micropsychotic episodes. The histrionic pt is dramatic, engaging, seductive, and attention-seeking. The narcissistic pt is self-centered and has an inflated sense of self-importance combined with a tendency to devalue or demean others, while pts with antisocial personality disorder use other people to achieve their own ends and engage in exploitative and manipulative behavior with no sense of remorse. Some aspects of the Cluster B personality disorders appear related to mood disorders.
Cluster C Personality Disorders
Patients with these disorders are often “whiny” or “sad.” The dependent pt fears separation, tries to engage others to assume responsibility, and often has a help- rejecting style. Pts with compulsive personality disorder are meticulous and perfectionistic but also inflexible and indecisive, while those who are passive- aggressive request help, appear compliant on the surface, but undo or resist all efforts aimed at change. Avoidant pts are anxious about social contact and have difficulty assuming responsibility for their isolation. The personality disorders share some features with the anxiety disorders

* Diagnostic and Statistical Manual, Fourth Edition, American Psychiatric Association
Bibliography

For a more detailed discussion, see Reus VI: Mental Disorders, Chap. 385, p. 2542, in HPIM-15.

Leave a comment

197 MUSCLE DISEASES
Harrison’s Manual of Medicine

197

MUSCLE DISEASES

Muscular Dystrophies

Duchenne Dystrophy

Myotonic Dystrophy

Facioscapulohumeral Dystrophy

Limb-Girdle Dystrophy

Oculopharyngeal Dystrophy (Progressive External Ophthalmoplegia)
Inflammatory Myopathies
Metabolic Myopathies
Mitochondrial Myopathies
Periodic Paralyses
Miscellaneous Disorders
Bibliography

Muscle diseases usually present as intermittent or persistent weakness. These disorders are usually painless; however, myalgias, or muscle pains, may occur. Myalgias must be distinguished from muscle cramps, i.e., painful muscle contractions, usually due to neurogenic disorders. A muscle contracture due to an inability to relax after an active muscle contraction is associated with energy failure in glycolytic disorders. Myotonia is a condition of prolonged muscle contraction followed by slow muscle relaxation. It is important to distinguish between true muscle weakness and a complaint of fatigue; fatigue without abnormal clinical or laboratory findings almost never indicates a true muscle disorder. An approach to pts with muscle weakness is summarized in Fig. 197-1 and Fig. 197-2.

FIGURE 197-1. Diagnostic evaluation for intermittent weakness. EOMs, extraocular muscles; AChR AB, acetylcholine receptor antibody; PP, periodic paralysis, CPT, carnitine palmityl transferase; MG, myasthenia gravis.

FIGURE 197-2. Diagnostic evaluation for persistent weakness. EOM, extraocular muscle; OPMD, oculopharyngeal muscular dystrophy; FSHD, facioscapulohumeral muscular dystrophy; IBM, inclusion body myositis; DM, dermatomyositis; PM, polymyositis; MG, myasthenia gravis, ALS, amyotrophic lateral sclerosis; CK, creatine kinase.

MUSCULAR DYSTROPHIES
A group of inherited, progressive degenerations of muscle that vary widely in their clinical and pathologic features and mode of inheritance.
Duchenne Dystrophy
X-linked recessive mutation of the dystrophin gene that affects males almost exclusively. Onset is by age 5; symmetric and progressive weakness in hip and shoulder girdle muscles leading to difficulty in climbing, running, jumping, hopping, etc. By age 8–10, most children require leg braces; by age 12, the majority are nonambulatory. Survival beyond age 25 is rare. Becker dystrophy is a less severe form, with a slower course and later age of onset (5–15) but similar clinical, laboratory, and genetic features.
Associated problems include tendon and muscle contractures (e.g., heel cords), progressive kyphoscoliosis, impaired pulmonary function, cardiomyopathy, and intellectual impairment. Palpable enlargement and firmness of some muscles (e.g., calves) results initially from hypertrophy and later from replacement of muscle by fat and connective tissue.
Laboratory Findings   Include massive elevations (20–100 × normal) of muscle enzymes (CK, aldolase), a myopathic pattern on EMG testing, and evidence of groups of necrotic muscle fibers with regeneration, phagocytosis, and fatty replacement of muscle on biopsy. Diagnosis is established by determination of dystrophin in muscle tissue by western blot and/or immunochemical staining. Mutations in the dystrophin gene can be identified in approximately two-thirds of pts using a battery of cDNA probes. ECG abnormalities (increased net RS in V1, deep Q in precordial leads) reflect the presence of cardiomyopathy. Serum CK is elevated in 50% of female carriers. Testing is now available for detecting carriers and prenatal diagnosis.

TREATMENT
Glucocorticoids [prednisone, 0.75 (mg/kg)/d] may significantly alter progression of disease for up to 3 years, but complications of chronic use often outweigh the benefits. Passive stretching of muscles, tenotomy, bracing, physiotherapy, mechanical assistance devices, and avoidance of prolonged immobility provide symptomatic benefit.

Myotonic Dystrophy
The most common adult muscular dystrophy. Autosomal dominant with genetic anticipation. Weakness typically becomes obvious in the second to third decade and initially involves the muscles of the face, neck, and distal extremities. This results in a distinctive facial appearance (“hatchet face”) characterized by ptosis, temporal wasting, drooping of the lower lip, and sagging of the jaw. Myotonia manifests as a peculiar inability to relax muscles rapidly following a strong exertion (e.g., after tight hand grip), as well as by sustained contraction of muscles following percussion (e.g., of tongue or thenar eminence).
Associated problems can include frontal baldness, posterior subcapsular cataracts, gonadal atrophy, respiratory and cardiac problems, endocrine abnormalities, intellectual impairment, and hypersomnia. Cardiac complications, including complete heart block, may be life-threatening. Respiratory function should be carefully followed, as chronic hypoxia may lead to cor pulmonale.
Laboratory Studies   Normal or mildly elevated CK, characteristic myotonia and myopathic features on EMG, and a typical pattern of muscle fiber injury on biopsy, including selective type I fiber atrophy. Pts have an unstable region of DNA with an increased number of trinucleotide CTG repeats at chromosome location 19q13.3. The expanded repeat may alter expression of a nearby protein kinase gene. Genetic testing for early detection and prenatal diagnosis is possible.

TREATMENT
Phenytoin, procainamide, and quinine may help myotonia, but they must be used carefully in pts with heart disease as they may worsen cardiac conduction. Pacemaker insertion may be required for syncope or heart block. Orthoses may control foot drop, stabilize the ankle, and decrease falling.

Facioscapulohumeral Dystrophy
An autosomal dominant, slowly progressive disorder with onset in the third to fourth decade. Weakness involves facial, shoulder girdle, and proximal arm muscles and can result in atrophy of biceps, triceps, scapular winging, and slope shoulders. Facial weakness results in inability to whistle and loss of facial expressivity. Foot drop and leg weakness may cause falls and progressive difficulty with ambulation.
Laboratory Studies   Normal or slightly elevated CK and mixed myopathic- neuropathic features on EMG and muscle biopsy. Pts have deletions at chromosome 4q35. A genetic probe can be used in carrier detection and prenatal diagnosis. Orthoses and other stabilization procedures may be of benefit for selected pts.
Limb-Girdle Dystrophy
A constellation of diseases with proximal muscle weakness involving the arms and legs as the core symptom. Age of onset, rate of progression, severity of manifestations, inheritance pattern (autosomal dominant or autosomal recessive) and associated complications (e.g., cardiac, respiratory) vary with the specific subtype of disease. Laboratory findings include elevated CK and myopathic features on EMG and muscle biopsy. At least eight autosomal recessive forms have been identified by molecular genetic analysis.
Oculopharyngeal Dystrophy (Progressive External Ophthalmoplegia)
Onset in the fifth to sixth decade of ptosis, limitation of extraocular movements, and facial and cricopharyngeal weakness. Most patients are Hispanic or of French-Canadian descent.
INFLAMMATORY MYOPATHIES
The most common group of acquired and potentially treatable skeletal muscle disorders. Three major forms: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Usually present as progressive and symmetric muscle weakness; extraocular muscles spared but pharyngeal weakness and neck drop common. IBM is characterized by early involvement of quadriceps and distal muscles. Progression is over weeks or months in PM and DM, but typically over years in IBM. Skin involvement in DM may consist of a heliotrope rash (blue-purple discoloration) on the upper eyelids with edema, a flat red rash on the face and upper trunk, or erythema over knuckles. A variety of cancers, including ovarian, breast, melanoma, and colon cancer, are associated with DM. Diagnostic criteria are summarized in Table 197-1.

Table 197-1 Criteria for Definite Diagnosis of Inflammatory Myopathies

TREATMENT
Often effective for PM and DM but not for IBM. Step 1: Glucocorticoids [prednisone, 1 (mg/kg)/d for 3–4 weeks, then tapered very gradually]; step 2: Azathioprine [up to 3 (mg/kg)/d] or methotrexate (7.5 mg/week gradually increasing to 25 mg/week); step 3: Intravenous immunoglobulin (2 g/kg divided over 2–5 d); step 4: Cyclosporine, chlorambucil, cyclophosphamide, or mycophenolate mofetil. IBM is generally resistant to immunosuppressive therapies; many experts recommend a short trial of glucocorticoids together with azathioprine or methotrexate.

METABOLIC MYOPATHIES
These disorders result from abnormalities in utilization by muscle of glucose or fatty acids as sources of energy. Pts present with either an acute syndrome of myalgia, myolysis, and myoglobinuria or chronic progressive muscle weakness. Definitive diagnosis requires biochemical-enzymatic studies of biopsied muscle. However, muscle enzymes, EMG, and muscle biopsy are all typically abnormal and may suggest specific disorders.
Glycogen storage disorders can mimic muscular dystrophy or polymyositis. In some types the presentation is one of episodic muscle cramps and fatigue provoked by exercise. The ischemic forearm lactate test is helpful as normal postexercise rise in serum lactic acid does not occur. In adults, progressive muscle weakness beginning in the third or fourth decade can be due to the adult form of acid maltase deficiency, or debranching enzyme deficiency. Exercise intolerance with recurrent myoglobinuria may be due to myophosphorylase deficiency (McArdle’s disease) or phosphofructokinase deficiency. Disorders of fatty acid metabolism present with similar clinical picture. In adults, the most common cause is carnitine palmitoyltransferase deficiency. Exercise-induced cramps, myolysis, and myoglobinuria are common; the picture can resemble polymyositis or muscular dystrophy. Some pts benefit from special diets (medium-chain triglyceride-enriched), oral carnitine supplements, or glucocorticoids.
MITOCHONDRIAL MYOPATHIES
More accurately referred to as mitochondrial cytopathies because multiple tissues are usually affected, these disorders result from defects in mitochondrial DNA. The clinical presentations vary enormously: muscle symptoms may include weakness, ophthalmoparesis, pain, stiffness, or may even be absent; age of onset ranges from infancy to adulthood; associated clinical presentations include ataxia, encephalopathy, seizures, strokelike episodes, and recurrent vomiting. The characteristic finding on muscle biopsy is “ragged red fibers,” which are muscle fibers with accumulations of abnormal mitochondria. Genetics show a maternal pattern of inheritance because mitochondrial genes are inherited almost exclusively from the oocyte.
PERIODIC PARALYSES
Characterized by muscle stiffness due to electrical irritability of the muscle membrane (myotonia), usually without significant muscle weakness until late in the course. Onset is usually in childhood or adolescence. Episodes typically occur after rest or sleep, often following earlier exercise. May be due to genetic disorders of calcium (hypokalemic periodic paralysis), sodium (hyperkalemic period paralysis), or chloride channels. Acute attacks of hypokalemic periodic paralysis are treated with potassium chloride, and prophylaxis with acetazolamide (125–1000 mg/d in divided doses) or dichorphenamide (50–200 mg/d) is usually effective.
MISCELLANEOUS DISORDERS
Myopathies may be associated with endocrine disorders, especially those involving hypo- or hyperfunction of the thyroid, parathyroid, pituitary, and adrenal glands. Drugs (esp. glucocorticoids) and certain toxins (e.g., alcohol) are commonly associated with myopathies (Table 197-2), as are deficiencies of vitamins D and E. In most cases weakness is symmetric and involves proximal limb girdle muscles. Weakness, myalgia, and cramps are common symptoms. Diagnosis often depends on resolution of signs and symptoms with correction of underlying disorder or removal of offending agent.

Table 197-2 Toxic Myopathies

Bibliography

For a more detailed discussion, see Mendell JR: Approach to the Patient with Muscle Disease, Chap. 381, p. 2520; Dalakas MC: Polymyositis, Dermatomyositis, and Inclusion Body Myositis, Chap. 382, p. 2524; Brown RH Jr., Mendell JR: Muscular Dystrophies and Other Muscle Diseases, Chap. 383, p. 2529, in HPIM-15.

Leave a comment

196 MYASTHENIA GRAVIS (MG)

196 MYASTHENIA GRAVIS (MG)
Harrison’s Manual of Medicine

196

MYASTHENIA GRAVIS (MG)

Clinical Features
Pathophysiology
Differential Diagnosis
Laboratory Evaluation
Bibliography

An autoimmune neuromuscular disorder resulting in weakness and fatiguability of skeletal muscles, due to autoantibodies directed against acetylcholine receptors (AChRs) at neuromuscular junctions (NMJs).
Clinical Features
May present at any age. Symptoms fluctuate throughout the day and are provoked by exertion. Characteristic distribution: cranial muscles (lids, extraocular muscles, facial weakness, “nasal” or slurred speech, dysphagia); in 85%, limb muscles (often proximal and asymmetric) become involved. Reflexes and sensation normal. May be limited to extraocular muscles only—particularly in elderly. Complications: aspiration pneumonia (weak bulbar muscles), respiratory failure (weak chest wall muscles), exacerbation of myasthenia due to administration of drugs with neuromuscular junction blocking effects (tetracycline, aminoglycosides, procainamide, propranolol, phenothiazines, lithium).
Pathophysiology
Specific anti-AChR antibodies reduce the number of AChRs at the NMJ. Postsynaptic folds are flattened or “simplified,” with resulting inefficient neuromuscular transmission. During repeated or sustained muscle contraction, decrease in amount of ACh released per nerve impulse, combined with decrease in postsynaptic AChRs, results in pathologic fatigue. Thymus is abnormal in 75% of pts (65% hyperplasia, 10% thymoma). Other autoimmune diseases in 10%; thyroiditis, Graves’ disease, rheumatoid arthritis, lupus erythematosus, red cell aplasia.
Differential Diagnosis

1.
Lambert-Eaton syndrome (autoantibodies to calcium channels in presynaptic motor nerve terminals)—reduced ACh release; associated with malignancy or idiopathic

2.
Neurasthenia—weakness/fatigue without underlying organic disorder

3.
Penicillamine may cause MG; resolves weeks to months after discontinuing drug

4.
Hyperthyroidism

5.
Botulism—toxin inhibits presynaptic ACh release

6.
Intracranial mass lesion—compression of nerves to extraocular muscles

7.
Progressive external ophthalmoplegia—seen in mitochondrial disorders
Laboratory Evaluation

AChR antibodies—no correlation with disease severity; 80% of all MG patients positive; 50% with ocular findings only are positive; positive antibodies are diagnostic.

Tensilon (edrophonium) test—a short-acting anticholinesterase—look for rapid and transient improvement of strength; false-positive (placebo response, motor neuron disease) and false-negative tests occur.

EMG—low frequency (2–4 Hz) repetitive stimulation produces decrement in amplitude of evoked motor responses.

Chest CT/MRI—search for thymoma.

Consider thyroid and other studies (e.g., ANA) for associated autoimmune disease.

TREATMENT
(See Fig. 196-1) The anticholinesterase drug pyridostigmine (Mestinon) titrated to assist pt with functional activities (chewing, swallowing, strength during exertion); usual initial dose of 60 mg 3–5 times daily; long-acting tablets help at night. Muscarinic side effects (diarrhea, abdominal cramps, salivation, nausea) blocked with propantheline if required. Plasmapheresis and IV immune globulin [IVIg; 400 (mg/kg)/d × 5 d] provide temporary boost for seriously ill pts; used to improve condition prior to surgery or during myasthenic crisis (severe exacerbation of weakness). Thymectomy improves likelihood of long-term remission in adult (less consistently in elderly) pts. Glucocorticoids are a mainstay of treatment; begin prednisone at low dose (15–25 mg/d), increase by 5 mg/d q2–3 d until marked clinical improvement or dose of 50 mg/d is reached. Maintain high dose for 1–3 months, then decrease to alternate-day regimen. Long-term treatment with low-dose prednisone usual. Immunosuppressive drugs (azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide) may spare dose of prednisone required to control symptoms; azathioprine [2–3 (mg/kg)/d] most often used. Myasthenic crisis is defined as an exacerbation of weakness, usually with respiratory failure, sufficient to endanger life; expert management in an intensive care setting essential.

FIGURE 196-1. Algorithm for the management of myasthenia gravis. FVC, forced vital capacity. (From DM Drachman: HPIM-15, p. 2518)

Bibliography

For a more detailed discussion, see Drachman DB: Myasthenia Gravis and Other Diseases of the Neuromuscular Junction, Chap. 380, p. 2515, in HPIM-15.

Leave a comment

195 PERIPHERAL NEUROPATHIES INCLUDING GUILLAIN-BARRé SYNDROME

195 PERIPHERAL NEUROPATHIES INCLUDING GUILLAIN-BARRé SYNDROME
Harrison’s Manual of Medicine

195

PERIPHERAL NEUROPATHIES INCLUDING GUILLAIN-BARRé SYNDROME

Polyneuropathy
Mononeuropathy
Bibliography

Peripheral neuropathy (PN) refers to a peripheral nerve disorder of any cause. Nerve involvement may be single (mononeuropathy) or multiple (polyneuropathy); pathology may be axonal or demyelinating. An approach to pts with suspected neuropathy appears in Fig. 195-1.

FIGURE 195-1. Approach to the evaluation of peripheral neuropathies, CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; EDX, electrodiagnostic studies; GBS, Guillain- Barré syndrome; IVIg, intravenous immunoglobulin. (After AK Asbury, in Harrison’s Textbook of Internal Medicine, Update IV, New York, McGraw-Hill, 1983.)

POLYNEUROPATHY
CLINICAL FEATURES   The typical axonal polyneuropathy begins with sensory symptoms (tingling or burning) distally in the toes or feet. Symptoms spread proximally to the ankles, then involve the calves. Ankle reflexes are lost. Once sensory loss reaches the knees, proximal spread extends into the thighs and numbness of fingers appears. This pattern results in a “stocking-glove” distribution of sensory and motor findings. Further progression results in loss of knee reflexes. Light touch may be perceived as uncomfortable (allodynia) or pinprick as excessively painful (hyperpathia). Weakness and atrophy evolve from distal to proximal—initial toe dorsiflexion weakness may progress to bilateral foot drop, intrinsic hand muscle weakness, or (in extreme cases) impairment of muscles needed for ventilation and sphincter function. A family history for neuropathy should be sought, since adult-onset hereditary motor and sensory neuropathy (HMSN II) is not uncommon. In contrast to axonal neuropathy, demyelinating neuropathy does not produce stocking-glove deficits; diffuse loss of reflexes and strength is usual, and nerves are often palpably enlarged.
DIAGNOSTIC EVALUATION   Diagnosis is aided by classification into axonal or demyelinating pathology (Table 195-1) and consideration of the time course of the neuropathy (Table 195-2). EMG is particularly helpful when history and examination do not clarify the diagnosis. EMG can distinguish axonal from demyelinating neuropathy, neuropathy from myopathy, nerve root or plexus disorders from distal nerve involvement, generalized polyneuropathy from mononeuropathy multiplex, and central weakness from peripheral nerve weakness. Sural nerve biopsy is helpful when vasculitis, multifocal demyelination, amyloidosis, leprosy, or sarcoidosis are considerations; biopsy results in lateral foot sensory loss, and rarely a painful neuroma may form at the biopsy site. Screening laboratory studies in a distal, symmetric axonal polyneuropathy are Hb A1C, ESR, serum protein/immunoelectrophoresis, and vitamin B12, BUN, and creatinine levels. Other studies are suggested by the differential diagnosis; it is important to recall that many systemic diseases, drugs, and toxins can produce neuropathy.

Table 195-1 Polyneuropathies (PN)a

Table 195-2 Diagnostic Considerations in Polyneuropathy

SPECIFIC POLYNEUROPATHIES

1.
Acute inflammatory demyelinating polyneuropathy (AIDP) or Guillain- Barré syndrome (GBS): an ascending, usually demyelinating, motor > sensory polyneuropathy accompanied by areflexia, motor paralysis, and elevated CSF total protein without pleocytosis. Over two-thirds are preceded by infection with EBV or other herpesviruses, Campylobacter jejuni gastroenteritis, HIV, other viruses, or Mycoplasma. Maximum weakness is usually reached within 2 weeks; demyelination by EMG. Most pts are hospitalized; one-third require ventilatory assistance. 85% make a complete or near-complete recovery with supportive care. Intravenous immune globulin (IVIg) (2 g/kg given over 5 d) or plasmapheresis (40–50 mL/kg daily for 4–5 d) significantly shorten the course. Glucocorticoids are ineffective. Variants of GBS include Fisher syndrome (ophthalmoparesis, facial diplegia, ataxia, areflexia; associated with antibodies to ganglioside GQ1b) and acute motor axonal neuropathy (more severe course than demyelinating GBS; antibodies to GM1 in some cases).

2.
Chronic inflammatory demyelinating polyneuropathy (CIDP): a slowly progressive or relapsing polyneuropathy characterized by diffuse hyporeflexia or areflexia, diffuse weakness, elevated CSF protein without pleocytosis, and demyelination by EMG. Begin treatment when progression is rapid or walking is compromised. Initial treatment is usually IVIg; most pts require periodic retreatment at 6-week intervals. Other treatment options include plasmapheresis or glucocorticoids; immunosuppressants (azothiaprine, methotrexate, cyclophosphamide) used in refractory cases.

3.
Diabetic neuropathy: typically a distal symmetric, sensorimotor, axonal polyneuropathy, but many variations occur. A mixture of demyelination and axonal loss is frequent. Isolated sixth or third cranial nerve palsies, asymmetric proximal motor neuropathy in the legs, truncal neuropathy, autonomic neuropathy, and an increased frequency of entrapment neuropathy at common sites of nerve compression all occur.

4.
Mononeuropathy multiplex (MM): defined as involvement of multiple noncontiguous nerves. One-third of adults with MM have an acquired demyelinating disorder that is treatable. The remainder have an axonal disorder; 50% of these have vasculitis—usually due to a connective tissue disorder. In this latter group, immunosuppressive treatment of the underlying disease is indicated.
MONONEUROPATHY
CLINICAL FEATURES   Mononeuropathies are usually caused by trauma, compression, or entrapment. Sensory and motor symptoms are in the distribution of a single nerve—most commonly ulnar or median nerves in the arms or peroneal nerve in the leg. Clinical features favoring conservative management of median neuropathy at the wrist (carpal tunnel syndrome) or ulnar neuropathy at the elbow include sudden onset, no motor deficit, few or no sensory findings (pain or paresthesia may be present), and no evidence of axonal loss by EMG. Factors favoring surgical decompression include chronic course (lack of response to conservative treatment), motor deficit, and electrodiagnostic evidence of axonal loss. Patterns of weakness, sensory loss, and conservative/ surgical treatment options are listed in Table 195-3.

Table 195-3 Common Mononeuropathies—Findings and Treatment

Bibliography

For a more detailed discussion, see Asbury AK: Approach to the Patient With Peripheral Neuropathy, Chap. 377, p. 2498; and Asbury AK, Hauser SL: Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies, Chap. 378, p. 2507, in HPIM-15.

Leave a comment

194 SPINAL CORD DISEASES

194 SPINAL CORD DISEASES
Harrison’s Manual of Medicine

194

SPINAL CORD DISEASES

Symptoms and Signs
Specific Signs by Spinal Cord Level
Intramedullary and Extramedullary Syndromes
Acute and Subacute Spinal Cord Diseases
Chronic Myelopathies
Complications
Bibliography

Diseases of the spinal cord can be devastating, but many are treatable if recognized early (Table 194-1). A working knowledge of relevant spinal cord anatomy is often the key to correct diagnosis (Fig. 194-1).

Table 194-1 Some Treatable Spinal Cord Disorders

FIGURE 194-1. Transverse section through the spinal cord, composite representation, illustrating the principal ascending (left) and descending (right) pathways. The lateral and ventral spinothalamic tracts (dark blue) ascend contralateral to the side of the body that is innervated. C, cervical; T, thoracic; L, lumbar; S, sacral, P, proximal; D, distal; F, flexors, E, extensors.

Symptoms and Signs
Principal signs are loss of sensation below a horizontal meridian on the trunk (“sensory level”), accompanied by weakness and spasticity.
Sensory Symptoms   Often paresthesia; may begin in one or both feet and ascend. Sensory level to pin sensation or vibration often correlates well with location of transverse lesions. May have isolated pain/temperature sensation loss over the shoulders (“cape” or “syringomyelic” pattern) or loss of sensation to vibration/position on one side of the body and pain/temperature loss on the other (Brown-Séquard hemicord syndrome).
Motor Impairment   Disruption of corticospinal tracts causes quadriplegia or paraplegia with increased muscle tone, hyperactive deep tendon reflexes, and extensor plantar responses. With acute severe lesions there may be initial flaccidity and areflexia (spinal shock).
Segmental Signs   These are approximate indicators of level of lesion, e.g., band of hyperalgesia/hyperpathia, isolated flaccidity, atrophy, or single lost tendon reflex.
Autonomic Dysfunction   Primarily urinary retention; should raise suspicion of spinal cord disease when associated with back or neck pain, weakness, and/or a sensory level.
Pain   Midline back pain is of localizing value; interscapular pain may be first sign of midthoracic cord compression; radicular pain may mark site of more laterally placed spinal lesion; pain from lower cord (conus medullaris) lesion may be referred to low back.
Specific Signs by Spinal Cord Level
Lesions Near the Foramen Magnum   Weakness of the ipsilateral shoulder and arm, followed by weakness of ipsilateral leg, then contralateral leg, then contralateral arm, with respiratory paralysis.
Cervical Cord   Best localized by noting pattern of motor weakness and areflexia; shoulder (C5), biceps (C5-6), brachioradialis (C6), triceps/finger and wrist extensors (C7), finger flexors (C8).
Thoracic Cord   Localized by identification of a sensory level on the trunk.
Lumbar Cord   Upper lumbar cord lesions paralyze hip flexion and knee extension, whereas lower lumbar lesions affect foot and ankle movements, knee flexion, and thigh extension.
Sacral Cord (Conus Medullaris)   Saddle anesthesia and early bladder/ bowel/sexual dysfunction.
Cauda Equina   Lesions below spinal cord termination at the L1 vertebral level produce a flaccid, areflexic, asymmetric paraparesis with bladder/bowel dysfunction and sensory loss below L1; pain is common and projected to perineum or thighs.
Intramedullary and Extramedullary Syndromes
Spinal cord disorders may be intramedullary (arising from within the substance of the cord) or extramedullary (compressing the cord or its blood supply). Extramedullary lesions often produce radicular pain, early corticospinal signs, and sacral sensory loss. Intramedullary lesions produce poorly localized burning pain, less prominent corticospinal signs, and often spare perineal/sacral sensation.
Acute and Subacute Spinal Cord Diseases
Commonly due to spinal cord compression (by tumor, infection, spondylosis, or trauma), infarction or hemorrhage, inflammation, or infection. Evaluation consists of MRI scans that provide excellent resolution of the spinal cord and identify most compressive lesions. Plain x-rays or CT of spine may be useful to assess presence of fractures and alignment of vertebral column. CSF analysis useful for infectious and inflammatory processes.

1.
Tumors of spinal cord: May be metastatic or primary, epidural or intradural; most are epidural metastases from adjacent vertebra. Malignancies commonly responsible: breast, lung, prostate, lymphoma, and plasma cell dyscrasias. Initial symptom is commonly back pain, worse when recumbent, with local tenderness preceding other symptoms by many weeks. Spinal cord compression due to metastases is a medical emergency; in general, therapy will not reverse paralysis of >48 h duration. Treatment consists of glucocorticoids (dexamethasone 40 mg daily) to reduce interstitial edema, local radiotherapy initiated as early as possible to the symptomatic lesion, and specific therapy for the underlying tumor type. Intradural tumors are generally benign—meningiomas or neurofibromas; treatment is surgical resection.

2.
Spinal epidural abscess: Triad of fever, localized spinal pain, and myelopathy (progressive weakness and bladder symptoms); once neurologic signs appear, cord compression rapidly progresses. Treatment is emergency decompressive laminectomy with debridement combined with long-term antibiotic therapy.

3.
Spinal epidural hemorrhage and hematomyelia: Presents as acute transverse myelopathy evolving over minutes or hours with severe pain. Causes: minor trauma, LP, anticoagulation, hematologic disorder, AV malformation, hemorrhage into tumor—most are idiopathic. Treatment is surgical evacuation and correction of any underlying bleeding disorder.

4.
Acute disk protrusion: Cervical and thoracic disk herniations are less common than lumbar.

5.
Acute trauma with spinal fracture/dislocation: May not produce myelopathy until mechanical stress further displaces destabilized spinal column.

6.
Inflammatory myelopathies: Acute transverse myelitis presents as sensory and motor symptoms, often with bladder involvement, evolving over hours to days. May follow infection, vaccination, or be the first sign of multiple sclerosis. Glucocorticoids, consisting of IV methylprednisolone followed by oral prednisone (Chap. 187), are indicated for moderate to severe symptoms. Rarely, a rapidly ascending necrotic myelopathy may occur as a paraneoplastic syndrome.

7.
Infectious myelopathies: Herpes zoster is the most common viral agent; schistosomiasis is an important cause worldwide.

8.
Spinal cord infarction: Anterior spinal artery infarction produces paraplegia or quadriplegia, dissociated sensory loss affecting pain/temperature and sparing vibration/position sensations (supplied by posterior spinal arteries), and loss of sphincter control. Associated conditions: aortic atherosclerosis, dissecting aortic aneurysm, hypotension. Treatment is symptomatic.
Chronic Myelopathies

1.
Spondylitic myelopathies: Presents as neck and shoulder pain, radicular arm pain, and progressive spastic paraparesis with paresthesia and loss of vibration sense; in advanced cases, urinary incontinence may occur. Results from combinations of disk bulging, osteophytic spur formation, partial subluxation, and hypertrophy of the dorsal spinal ligament. Treatment is surgical (Chap. 5).

2.
Vascular malformations: An important treatable cause of progressive myelopathy. May occur at any level; diagnosis is made by contrast-enhanced MRI, confirmed by selective spinal angiography. Treatment is embolization with occlusion of the major feeding vessels.

3.
Retrovirus-associated myelopathies: Infection with HTLV-I or HTLV- II may produce a slowly progressive spastic paraparesis with variable pain, sensory loss, and bladder disturbance; diagnosis is made by demonstration of specific serum antibody. Treatment is symptomatic. A progressive vacuolar myelopathy may also occur in AIDS.

4.
Syringomyelia: Cavitary expansion of the spinal cord resulting in progressive myelopathy; may be an isolated finding or associated with protrusion of cerebellar tonsils into cervical spinal canal (Chiari type 1) or with incomplete closure of spinal canal (Chiari type 2). Classic presentation is loss of pain/ temperature sensation in the neck, shoulders, forearms, or hands with areflexic weakness in the upper limbs and progressive spastic paraparesis; cough headache, facial numbness, or thoracic kyphoscoliosis may occur. Diagnosis is made by MRI; treatment is surgical.

5.
Multiple sclerosis: See Chap. 187.

6.
Subacute combined degeneration (vitamin B12 deficiency): Paresthesia in hands and feet, early loss of vibration/position sense, progressive spastic/ ataxic weakness, and areflexia due to associated peripheral neuropathy; mental changes (“megaloblastic madness”) may be present. Diagnosis is confirmed by a low serum B12 level and a positive Schilling test. Treatment is vitamin replacement.

7.
Tabes dorsalis: May present as lancinating pains, gait ataxia, bladder disturbances, and visceral crises. Cardinal signs are areflexia in the legs, impaired vibration/position sense, Romberg’s sign, and Argyll Robertson pupils, which fail to constrict to light but react to accommodation.

8.
Familial spastic paraplegia: Progressive spasticity and weakness in the legs occurring on a familial basis; may be autosomal dominant, recessive, or X-linked.
Complications
Damage to urinary tract due to urinary retention with bladder distention and injury to detrusor muscle; UTI; paroxysmal hypertension or hypotension with volume changes; ileus and gastritis; in high cervical cord lesions, mechanical respiratory failure; severe hypertension and bradycardia in response to noxious stimuli or bladder or bowel distention; pressure sores; venous thrombosis and pulmonary embolism.
Bibliography

For a more detailed discussion, see Hauser SL: Diseases of the Spinal Cord, Chap. 368, p. 2425, in HPIM-15.

Leave a comment

193 AUTONOMIC NERVOUS SYSTEM DISORDERS

193 AUTONOMIC NERVOUS SYSTEM DISORDERS
Harrison’s Manual of Medicine

193

AUTONOMIC NERVOUS SYSTEM DISORDERS

ANS Overview
Disorders of the ANS
Bibliography

The autonomic nervous system (ANS) regulates homeostatic functions critical to survival including blood pressure, blood flow, tissue perfusion, sweating, hunger, satiety, temperature, thirst, and circadian rhythms. The importance of this regulation is demonstrated by the severity of disability resulting from compromised ANS function.
ANS OVERVIEW
Key features of the ANS are summarized in Table 193-1. Responses to sympathetic (S) or parasympathetic (P) activation often have opposite effects; partial activation of both systems allows for simultaneous integration of multiple body functions.

Table 193-1 ANS Overview

Catecholamines exert their effects on two types of receptors, a and b. The a1 receptor mediates vasoconstriction. The a2 receptor mediates presynaptic inhibition of norepinephrine (NE) release from adrenergic nerves, inhibits acetylcholine (ACh) release from cholinergic nerves, inhibits lipolysis in adipocytes, inhibits insulin secretion, and stimulates platelet aggregation. The b1 receptor responds to both NE and epinephrine (E) and mediates cardiac stimulation and lipolysis. The b2 receptor is more responsive to E than NE and mediates vasodilatation and bronchodilation.
DISORDERS OF THE ANS
The CNS, peripheral nervous system, or both may be affected; disorders may be generalized (with or without CNS signs) or focal (Table 193-2). Clinical signs and symptoms are due to interruption of the afferent limb, CNS processing centers, or efferent limb of the reflex arc controlling the autonomic responses. Clinical manifestations are influenced by the organ involved, normal balance of sympathetic-parasympathetic innervation, nature of the underlying illness, and severity/stage of disease. Orthostatic hypotension (OH) is defined as a postural decrease in BP from the supine to standing position of at least 20 mmHg systolic or 10 mmHg diastolic BP sustained for at least 2 min. OH is often disabling. Syncope or near syncope results when the drop in BP impairs cerebral perfusion. Presyncopal symptoms that may appear on standing include light-headedness, dimming of vision, nausea, diminished hearing, hyperhidrosis, hypohidrosis, pallor, and weakness.

Table 193-2 Classification of ANS Disorders

Approach to the Patient

The evaluation of symptomatic OH begins with the exclusion of treatable causes. Most causes of OH are not due to nervous system disease (Table 193-3). In nonneurogenic OH, the drop in blood pressure with standing is usually associated with an appropriate, compensatory rise in heart rate, in contrast to neurogenic OH in which a compensatory rise in heart rate does not occur. History should include a review of medications (e.g., diuretics) and medical problems (e.g., diabetes). Exaggerated medication responses may be the first sign of underlying autonomic disorder. The relationship of symptoms to meals (splanchnic shunting of blood) and awakening in the morning (relative intravascular volume depletion) should be sought. Examination of mental status (e.g., neurodegenerative disorders), cranial nerves (e.g., impaired downgaze with progressive supranuclear palsy), motor function (e.g., parkinsonian syndromes), and sensory function (e.g., polyneuropathy) is necessary. Disorders of autonomic function need to be considered in the differential diagnosis of pts with impotence, bladder dysfunction (urinary frequency, hesitancy, or incontinence), diarrhea, constipation, or altered sweating (hyperhidrosis or hypohidrosis).

Table 193-3 Nonneurogenic Causes of Orthostatic Hypotension

Autonomic Testing
The most commonly used autonomic tests assess cardiovascular function; they are noninvasive, easy to administer, and provide quantitative information; normative data from healthy controls is essential. Heart rate variation with deep breathing is a measure of vagal function. The Valsalva maneuver measures changes in heart rate and blood pressure while a constant expiratory pressure of 40 mmHg for 15 s is maintained. The Valsalva ratio is calculated as the maximum heart rate during the maneuver divided by the minimum heart rate following the maneuver. The ratio reflects the integrity of the entire baroreceptor reflex arc and sympathetic efferents to blood vessels (Chap. 366, HPIM-15). Tilt-table beat-to-beat BP measurements in the supine, 80° tilt, and tilt-back positions can be used to evaluate orthostatic failure in BP control in pts with unexplained syncope.
Other tests of autonomic function include the quantitative sudomotor axon reflex test (QSART), the thermoregulatory sweat test (TST), and the cold pressor test. The QSART provides a quantitative, regional measure of sweating in response to iontophoresis of ACh. The TST provides a qualitative measure of regional sweating over the entire anterior surface of the body in response to a standardized elevation of body temperature. The cold pressor test is used to assess sympathetic efferent function. For a more complete discussion of autonomic function tests, see Chap. 366, HPIM-15.

SPECIFIC SYNDROMES OF ANS DYSFUNCTION   Diseases of the CNS may cause ANS dysfunction at the level of the hypothalamus, brainstem, or spinal cord (Table 193-1). Multiple system atrophy (MSA) refers to several overlapping CNS syndromes with a variable combination of symptoms and signs including postural hypotension, impotence, bladder and bowel dysfunc tion, defective sweating, rigidity, tremor, loss of associative movements, upper motor neuron signs, cerebellar signs, or abnormal eye movements. Pts may present with only one symptom or sign and later develop the full clinical spec trum of MSA.
Spinal cord injury may be accompanied by autonomic hyperreflexia affecting bowel, bladder, sexual, temperature regulation, or cardiovascular functions. Dangerous increases or decreases in body temperature may result from the inability to experience the sensory accompaniments of heat or cold exposure below the level of the injury. Markedly increased autonomic discharge (autonomic dysreflexia) can be elicited by bladder pressure or stimulation of the skin or muscles. Bladder distention from palpation, catheter insertion, catheter obstruction, or urinary infection are common and correctable causes of autonomic dysreflexia.
Peripheral neuropathies are the most common cause of chronic autonomic insufficiency (Chap. 366, HPIM-15). Autonomic involvement in diabetes mellitus may begin at any stage in the disease. Diabetic enteric neuropathy may result in gastroparesis, nausea and vomiting, malnutrition, and bowel incontinence. Impotence, urinary incontinence, pupillary abnormalities, and postural hypotension may occur as well. Prolongation of the QT interval may occur and enhances the risk of sudden death. Autonomic neuropathy occurs in both sporadic and familial forms of amyloidosis. Pts may present with distal, painful polyneuropathy. Cardiac or renal disease is the usual cause of death. Alcoholic polyneuropathy produces clinical symptoms of autonomic failure only when the signs of peripheral neuropathy are severe. BP fluctuation and cardiac arrhythmias can be severe in Guillain-Barré syndrome. Attacks of acute intermittent porphyria (AIP) are associated with tachycardia, sweating, urinary retention, and hypertension. Botulism is associated with blurred vision, dry mouth, nausea, unreactive pupils, urinary retention, and constipation. Postural orthostatic tachycardia syndrome (POTS) consists of symptoms of orthostatic intolerance—including shortness of breath, light-headedness, and exercise intolerance—accompanied by an increase in heart rate but no drop in BP. The importance of postprandial hypotension in healthy elderly persons and hypertensive pts taking BP medications with meals is drawing increasing attention. Primary hyperhidrosis affects 0.6–1.0% of the population; the usual symptoms are excessive sweating of the palms and soles. Onset is in adolescence, and symptoms tend to improve with age. Although not dangerous, this condition is socially embarrassing.
REFLEX SYMPATHETIC DYSTROPHY (RSD) AND CAUSALGIA   The role of the ANS in RSD and causalgia is controversial, and there is no generally accepted pathogenic mechanism to explain these disorders. The terms complex regional pain syndrome (CRPS) type I and CRPS type II have been proposed as substitutes for the terms RSD and causalgia, respectively.
In causalgia, spontaneous pain develops within the territory of an injured nerve and may spread outside, but contiguous to, the distribution of the affected nerve. Allodynia (the perception of a nonpainful stimulus as painful) and hyperpathia (an exaggerated pain response to a mildly painful stimulus) are common. RSD is a regional pain syndrome that develops after trauma. Unlike causalgia, limb symptoms are not confined to the distribution of a single peripheral nerve. Although pain is the primary feature of both causalgia and RSD, vasomotor, sudomotor, or edematous changes must be present to satisfy criteria for diagnosis. Treatment of both disorders is a difficult therapeutic challenge (Chap. 366 in HPIM-15).

TREATMENT
Management of autonomic failure is limited typically to alleviating disability caused by symptoms. A review of medications, relationship of symptoms to meals, medical illnesses, and other symptoms of possible autonomic origin is mandatory. Orthostatic hypotension requires treatment only if it causes symptoms. In early stages, pts can maintain normal function by using simple measures. Alcohol use and exposure to elevated temperature should be avoided because vaosdilatation can suddenly lower BP. Drugs that affect BP should be used with great caution. Salt intake should be increased to the maximum tolerated. Sleeping in reverse Trendelenburg position (head-up tilt) minimizes supine hypertension. Frequent, small meals may improve postprandial hypotension. Most pts require drug therapy for the management of neurogenic OH. Fludrocortisone (0.1 mg/d–0.3 mg bid PO) is the initial drug of choice; potassium supplementation is necessary with chronic administration. Midodrine (5 mg tid–10 mg q4h PO) is an a1 agonist approved by the FDA for treatment of neurogenic OH. Other drugs may be effective for postprandial OH (indomethacin, caffeine), OH associated with diarrhea (clonidine), and OH associated with anemia (erythropoietin). Many agents can be used to elevate BP, but supine hypertension or a lack of symptomatic improvement often limits their value. Management during anesthesia poses unique problems since pts may have abnormal baroreceptor reflexes, sympathetic innervation of peripheral arterioles, abnormal fluid balance, and adrenal medullary insufficiency.

Bibliography

For a more detailed discussion, see Engstrom JW, Martin JB: Disorders of the Autonomic Nervous System, Chap. 366, p. 2416, in HPIM-15.

1 Comment

192 CRANIAL NERVE DISORDERS

192 CRANIAL NERVE DISORDERS
Harrison’s Manual of Medicine

192

CRANIAL NERVE DISORDERS

Olfactory Nerve (I)
Trigeminal Nerve (V)
Facial Nerve (VII)
Glossopharyngeal Nerve (IX)
Vagus Nerve (X)
Hypoglossal Nerve (XII)
Multiple Cranial Nerve Palsies
Bibliography

Disorders of vision and ocular movement are discussed in Chap. 10 and Chap. 48; dizziness and vertigo in Chap. 9; and disorders of hearing in Chap. 49;
OLFACTORY NERVE (I)
The sense of smell may be impaired by (1) interference with access of odorant to olfactory neuroepithelium (transport loss), e.g., by swollen nasal mucous membrane in URI, allergic rhinitis, or structural changes in nasal cavity such as with a deviated septum, nasal polyps, or neoplasm; (2) injury to receptor region (sensory loss), e.g., destruction of olfactory neuroepithelium by viral infections, neoplasms, inhalation of toxic chemicals, or radiation to head; and (3) damage to central olfactory pathways (neural loss), e.g., by head trauma with or without fractures of cribriform plate, neoplasms of anterior cranial fossa, neurosurgical procedures, neurotoxic drugs, or congenital disorders such as Kallmann’s syndrome.
TRIGEMINAL NERVE (V) (See Fig. 192-1)

FIGURE 192-1. The three major sensory divisions of the trigeminal nerve consist of the ophthalmic, maxillary, and mandibular nerves.

Trigeminal Neuralgia (Tic Douloureux)   Frequent, excruciating paroxysms of pain in lips, gums, cheek, or chin (rarely in ophthalmic division of fifth nerve) lasting seconds to minutes. Appears in middle or old age. Pain is often stimulated at trigger points. Sensory deficit cannot be demonstrated. Must be distinguished from other forms of facial pain arising from diseases of jaw, teeth, or sinuses. Tic is rarely caused by herpes zoster or a tumor. Onset in young adulthood raises the possibility of multiple sclerosis.

TREATMENT
Carbamazepine is effective in 75% of cases. Begin at 100 mg single daily dose taken with food and advance by 100 mg every 1–2 days until substantial (50%) pain relief occurs. Most pts require 200 mg qid; doses >1200 mg daily usually provide no additional benefit. Follow CBC for rare complication of aplastic anemia. For nonresponders, phenytoin (300–400 mg qd) or baclofen (5–20 mg tid-qid) can be tried. When medications fail, surgical gangliolysis or suboccipital craniectomy for decompression of trigeminal nerve are options; in some centers, microvascular decompression is recommended if a tortuous or redundant blood vessel is found in the posterior fossa near the trigeminal nerve.

Trigeminal Neuropathy   Usually presents as facial sensory loss or weakness of jaw muscles. Causes are varied (Table 192-1) including tumors of middle cranial fossa or trigeminal nerve, metastases to base of skull, or lesions in cavernous sinus (affecting first and second divisions of fifth nerve) or superior orbital fissure (affecting first division of fifth nerve).

Table 192-1 Trigeminal Nerve Disorders

FACIAL NERVE (VII)
Lesions of the seventh nerve or nucleus produce hemifacial weakness that includes muscles of forehead and orbicularis oculi; if lesion is in middle ear portion, taste is lost over the anterior two-thirds of tongue and there may be hyperacusis; if lesion is at internal auditory meatus, there may be involvement of auditory and vestibular nerves, whereas pontine lesions usually affect abducens nerve and often corticospinal tract as well. Peripheral nerve lesions with incomplete recovery may result in diffuse continuous contraction of affected facial muscles +/– associated movements (synkinesis) of other facial muscle groups and facial spasms.
Bell’s Palsy   Most common form of idiopathic facial paralysis, found in 23/100,000 annually, or 1 in 60–70 persons over a lifetime. Pathogenesis uncertain, but an association with herpes simplex virus type 1 has been documented. Weakness evolves over 12–48 h, sometimes preceded by retroaural pain. Fully 80% recover within several weeks or months.

TREATMENT
Involves protection of eye with paper tape to depress the upper eyelid during sleep. Prednisone (60–80 mg qd over 5 d, tapered off over the next 5 d) when started early appears to shorten the recovery period and modestly improve functional outcome. In one study, treatment within 3 days of onset with both prednisone and acyclovir (400 mg five times daily for 10 d) improved outcome.

Other Facial Nerve Disorders   Ramsay Hunt Syndrome is caused by herpes zoster infection of geniculate ganglion; distinguished from Bell’s palsy by a vesicular eruption in pharynx, external auditory canal, and other parts of the cranial integument. Acoustic neuromas often compress the seventh nerve. Pontine tumors or infarcts may cause a lower motor neuron facial weakness. Bilateral facial diplegia may appear in Guillain-Barré syndrome, sarcoidosis, Lyme disease, and leprosy. Hemifacial spasm may result from Bell’s palsy, irritative lesions (e.g., acoustic neuroma, basilar artery aneurysm, or aberrant vessel compressing the nerve) or as an idiopathic disorder. Blepharospasm consists of involuntary recurrent spasms of both eyelids, usually occurring in the elderly and sometimes with associated facial spasm. May subside spontaneously. Severe cases of hemifacial spasm or blepharospasm can be treated by local injection of botulinus toxin into the orbicularis oculi; spasms are relieved for 3–4 months, and injections can be repeated.
GLOSSOPHARYNGEAL NERVE (IX)
Glossopharyngeal Neuralgia   Paroxysmal, intense pain in tonsillar fossa of throat that may be precipitated by swallowing. There is no demonstrable sensory or motor deficit. Other diseases affecting this nerve include herpes zoster or compressive neuropathy due to tumor or aneurysm in region of jugular foramen (when associated with vagus and accessory nerve palsies).

TREATMENT
Carbamazepine or phenytoin is often effective, but surgical division of the ninth nerve near the medulla is sometimes necessary.

VAGUS NERVE (X)
Lesions of vagus nerve cause symptoms of dysphagia and dysphonia. Unilateral lesions produce drooping of soft palate, loss of gag reflex, and “curtain movement” of lateral wall of pharynx with hoarse, nasal voice. Diseases that may involve the vagus include diphtheria (toxin), neoplastic and infectious processes of the meninges, tumors and vascular lesions in the medulla, or compression of the recurrent laryngeal nerve by intrathoracic processes.
HYPOGLOSSAL NERVE (XII)
The twelfth cranial nerve supplies the ipsilateral muscles of the tongue. Atrophy and fasciculations of the tongue develop weeks to months after interruption of the nerve. Lesions affecting the motor nucleus may occur in the brainstem (tumor, poliomyelitis, or motor neuron disease), during the course of the nerve in the posterior fossa (platybasia, Paget’s disease), or in the hypoglossal canal.
MULTIPLE CRANIAL NERVE PALSIES
The main clinical problem is to determine whether the process is within the brainstem or outside it. Lesions that lie on the surface of the brainstem tend to involve adjacent cranial nerves in succession with only late and slight involvement of long sensory and motor pathways within the brainstem. The opposite is true of processes within the brainstem. Involvement of multiple cranial nerves outside of the brainstem may be due to diabetes, trauma, infectious and noninfectious causes of meningitis; granulomatous diseases including sarcoidosis, tuberculosis, and Wegener’s granulomatosis; tumors; and enlarging saccular aneurysms. A purely motor disorder raises a question of myasthenia gravis. Facial diplegia is common in Guillain-Barré syndrome. Ophthalmoplegia may occur with Guillain-Barré syndrome (Fisher variant) or Wernicke’s disease. Involvement of the cavernous sinus (Fig. 192-2) may be due to infection, aneurysm, a carotid-cavernous fistula, nasopharyngeal carcinoma, or a granulomatous disease. Finally, an idiopathic multiple cranial nerve disorder may occur, consisting of boring unilateral or bilateral facial pain followed by paralysis of motor cranial nerves; inflammation of the dura mater may be visualized by MRI, and treatment is with glucocorticoids.

FIGURE 192-2. Anatomy of the cavernous sinus in coronal section, illustrating the location of the cranial nerves in relation to the vascular sinus, internal carotid artery (which loops anteriorly to the section), and surrounding structures.

Bibliography

For a more detailed discussion, see Beal MF, Hauser SL: Common Disorders of the Cranial Nerves, Chap. 367, p. 2421, in HPIM-15.

Leave a comment

191 ALS AND OTHER MOTOR NEURON DISEASE

191 ALS AND OTHER MOTOR NEURON DISEASES
Harrison’s Manual of Medicine

191

ALS AND OTHER MOTOR NEURON DISEASES

Etiology
Clinical History
Physical Examination
Laboratory Findings
Complications
Bibliography

Etiology
Amyotrophic lateral sclerosis (ALS) is the most important of the motor neuron diseases (Table 191-1). ALS is caused by degeneration of motor neurons at all levels of the CNS, including anterior horns of the spinal cord, brainstem motor nuclei, and motor cortex. Familial ALS (FALS) represents 5–10% of the total and is inherited as an autosomal dominant disorder. Syndromes clinically indistinguishable from classic ALS may result rarely from intoxication with mercury, lead, or aluminum and in hyperparathyroidism, thyrotoxicosis, immunologic or paraneoplastic mechanisms, and hereditary biochemical disorders. Tumors near the foramen magnum, high spinal cord tumors, cervical spondylosis, chronic polyradiculopathies, polymyositis, spinal muscle atrophies, and diabetic, syphilitic, and postpolio amyotrophies can all produce signs and symptoms similar to those seen in ALS and should be carefully considered in differential diagnosis (Table 191-2).

Table 191-1 Sporadic Motor Neuron Diseases

Table 191-2 Etiology and Investigation of Motor Neuron Disorders

Clinical History
Onset is usually midlife, with most cases progressing to death in 3–5 years. Common initial symptoms are weakness, muscle wasting, stiffness and cramping, and twitching in muscles of hands and arms. Legs are less severely involved than arms, with complaints of leg stiffness, cramping, and weakness common. Symptoms of brainstem involvement include dysarthria and dysphagia.
Physical Examination
Lower motor neuron disease results in weakness and wasting that often first involves intrinsic hand muscles but later becomes generalized. Fasciculations occur in involved muscles, and fibrillations may be seen in the tongue. Hyperreflexia, spasticity, and upgoing toes in weak, atrophic limbs provide evidence of upper motor neuron disease. Brainstem disease produces wasting of the tongue, difficulty in articulation, phonation, and deglutition, and pseudobulbar palsy (e.g., involuntary laughter, crying). Important additional features that characterize ALS are preservation of intellect, lack of sensory abnormalities, and absence of bowel or bladder dysfunction.
Laboratory Findings
EMG provides objective evidence of muscle denervation as well as of involvement of muscles innervated by different peripheral nerves and nerve roots. Myelography, CT, or MRI may be useful to exclude compressive lesions. CSF is usually normal. Muscle enzymes (e.g., CK) may be elevated. Pulmonary function studies may aid in management of ventilation. Useful tests to exclude other diseases can include urine and serum screens for heavy metals, thyroid functions, serum immunoelectrophoresis, lysosomal enzyme screens, anti-GM1 antibodies, vitamin B12 levels, VDRL, CBC, ESR, and serum chemistries. In FALS, one subset has mutations in the gene encoding the cytosolic enzyme superoxide dismutase 1 (SOD1).
Complications
Weakness of ventilatory muscles leads to respiratory insufficiency; dysphagia may result in aspiration pneumonia and compromised energy intake.

TREATMENT
There is no treatment capable of arresting ALS. The drug riluzole produces modest lengthening of survival; in one trial the survival rate at 18 months with riluzole (100 mg/d) was similar to placebo at 15 months. It may act by diminishing glutamate release and thereby decreasing excitotoxic neuronal cell death. Side effects of riluzole include nausea, dizziness, weight loss, and elevation of liver enzymes. In a single study, insulin-like growth factor (IGF- 1) was found to slow ALS progression modestly, but the effect was not confirmed in a second trial; IGF-1 is not routinely available as an ALS treatment at this time. Clinical trials of several other agents are in progress, including brain-derived neurotrophic factor, glial-derived neurotrophic factor, the anti- glutamate compound topiramate, and creatine. In a single study from France, vitamin E was beneficial in sporadic ALS. Several types of secondary motor neuron disorders that resemble ALS are treatable (Table 191-2). All pts should have a careful search for these disorders. Supportive care can include home care ventilation and pulmonary support; speech therapy; nonverbal, electronic, or mechanical communication systems for anarthric pts; and dietary management to ensure adequate energy intake. Attention to use of rehabilitative devices (braces, splints, canes, walkers, mechanized wheelchairs) is essential to improve care.

Bibliography

For a more detailed discussion, see Brown RH Jr: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases, Chap. 365, p. 2412, in HPIM- 15.

Leave a comment

190 ATAXIC DISORDERS

190 ATAXIC DISORDERS
Harrison’s Manual of Medicine

190

ATAXIC DISORDERS

Clinical Presentation
Inherited Ataxias
Evaluation
Bibliography

Clinical Presentation
Symptoms and signs of ataxia may include gait instability, nystagmus, dysarthria (scanning speech), impaired limb coordination, intention tremor (i.e., with movement), hypotonia. Differential diagnosis: Unsteady gait associated with vertigo can resemble gait instability of cerebellar disease but produces a sensation of head movement, dizziness, or light-headedness. Bilateral proximal leg weakness or sensory ataxia, in particular with neuropathies (e.g., Fisher variant of Guillain-Barré syndrome), can also simulate cerebellar ataxia.

Approach to the Patient

Causes are best grouped by determining whether ataxia is symmetric or asymmetric and by the time course (Table 190-1). It is also important to distinguish whether ataxia is present in isolation or is part of a multisystem neurologic disorder. Acute symmetric ataxia is usually due to medications, toxins, viral infection, or a postinfectious syndrome (especially varicella). Subacute or chronic symmetric ataxia can result from hypothyroidism, vitamin deficiencies, infections, alcohol, and other toxins. Progressive nonfamilial cerebellar ataxia after age 45 suggests a paraneoplastic syndrome, either subacute cortical cerebellar degeneration (ovarian, breast, small cell lung, Hodgkin’s) or opsoclonus- myoclonus (neuroblastoma, breast).

Table 190-1 Etiology of Cerebellar Ataxia

Unilateral ataxia suggests a focal lesion in the ipsilateral cerebellar hemisphere or its connections. An important cause of acute unilateral ataxia is stroke. Mass effect from cerebellar hemorrhage or swelling from ischemic cerebellar infarction can compress brainstem structures, producing altered consciousness and ipsilateral pontine signs (small pupil, lateral gaze or sixth nerve paresis, facial weakness); limb ataxia may not be prominent. Other diseases resulting in subacute-to-chronic unilateral or asymmetric ataxia include tumors, multiple sclerosis, progressive multifocal leukoencephalopathy (immunodeficiency states) or congenital malformations.

Inherited Ataxias
May be autosomal dominant, autosomal recessive, or mitochondrial (maternal inheritance); 24 different disorders recognized (Table 364-2, HPIM-15). Friedreich’s ataxia is most common; autosomal recessive; ataxia with areflexia, upgoing toes, vibration and position sensation deficits, cardiomyopathy, hammer toes, scoliosis; linked to expanded trinucleotide repeat in the intron of “frataxin” gene; a second genetic form of Friedreich’s is associated with vitamin E deficiency. Common dominantly inherited ataxias are spinocerebellar ataxia (SCA) 1 (olivopontocerebellar degeneration; “ataxin-1” gene) and SCA 3 (Machado-Joseph disease); both present with ataxia and brainstem and extrapyramidal signs; SCA 3 may also have dystonia and amyotrophy; genes for each disorder contain unstable trinucleotide repeats in coding region.
Evaluation
The differential diagnosis is driven by the symmetry and time course of the ataxia (Table 190-1). For symmetric ataxias, drug and toxicology screens; vitamin B1, B12, and E levels; thyroid function tests; antibody tests for syphilis and Lyme infection; paraneoplastic autoantibodies (anti-Yo, anti-Ri, anti-Hu); and CSF studies often indicated. Genetic testing is available for many inherited ataxias but should be carried out only with genetic counseling. For unilateral or asymmetric ataxias, brain MRI or CT scan is the initial test of choice.
Hypothyroidism, vitamin deficiency, infectious and parainfectious causes of ataxia are treatable. With paraneoplastic ataxias, identification of underlying cancer is important for the pt, but as a rule ataxia does not improve following treatment of tumor. Cerebellar hemorrhage and other mass lesions of the posterior fossa may require surgical treatment to prevent fatal brainstem compression.
Bibliography

For a more detailed discussion, see Rosenberg RN: Ataxic Disorders, Chap. 364, p. 2406, in HPIM-15.