RESTLESS LEG SYNDROME

RESTLESS LEG SYNDROME

Restless leg syndrome (RLS) is an idiopathic condition resulting in a sensation of creeping and crawling dysesthesia within the legs, leading to involuntary movements during sleep. Often the condition is brought to attention because of  multiple bruises sustained by the  sleep partner. The condition can be familial and is exacerbated by sleep deprivation, caffeine, and pregnancy. There is also an association with uremia, iron deficiency, and peripheral neuropathy.

There is no specific diagnostic test for this disorder. Treatment is a dopamine agonist such  as pramipexole or ropinirole, although some patients may need levodopa/carbidopa. Other therapies are narcotics and benzodiazepines.

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BENIGN ESSENTIAL TREMOR

BENIGN  ESSENTIAL TREMOR:

This is an idiopathic disorder consisting of an isolated tremor of the hands, head, or both. The lower extremities tend to be spared. Essential tremor can be worsened by the use of caf- feine or beta agonists. Examination reveals no other abnormalities. Although the level of dis- ability tends to be limited, there can be interference with manual skills such as the ability to write. It is characteristic of this disorder that there is an improvement with the use of alcohol. The patient will describe shaky hands, which improve with 2–3 drinks.

There is no specific diagnostic test for this disorder. Treatment is propranolol. If propranolol is ineffective, alternate medications are primidone, alprazolam, and clozapine. If no medical therapy is effective, thalamotomy is indicated.

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PARKINSON DISEASE

PARKINSON DISEASE

A 56-year-old man is brought to the office by his wife for evaluation of a resting tremor that she noticed recently. She also states that her husband has been moving “very slowly” as of late. When questioned, the patient states that he feels fine and does not know why his wife is dragging him from doctor to doctor. His past medical history is significant for mild hypertension that has been treated with a thiazide diuretic.

Physical examination is significant for a resting tremor noted in his right hand. When walking, the patient is stooped forward, taking small steps. You note cogwheel rigidity in his right upper extremity with a positive Myerson sign.

Definition. Parkinson disease is defined as a neurologic syndrome resulting from the deficiency of the neurotransmitter dopamine as a consequence of degenerative, vascular, or inflammatory changes in the basal ganglia.

Etiology. There are numerous causes of Parkinsonism. Many drugs can cause Parkinsonism, including neuroleptic agents (haloperidol, chlorpromazine), antiemetics (metoclopramide), alpha-methyldopa, and reserpine. Poisoning from MPTP, carbon monoxide, cyanide, and manganese are also causes of Parkinsonism. Any structural lesion around the basal ganglia (trauma, tumor, abscess, infarct) can produce clinical Parkinson disease. Patients who have survived an episode of encephalitis can develop postencephalitic Parkinsonism.

Clinical Presentation. The cardinal manifestations of Parkinson disease are bradykinesia (manifested by slow movements, mask facies, reduction of automatic movements), cog- wheel rigidity, postural instability, and resting tremor. A useful mnemonic is to think of Mr. Parkinson as a fine BRITish gentleman.

Bradykinesia Rigidity (cogwheel) Instability (postural) Tremor (resting)

There are a number of “Parkinson plus” syndromes, which are characterized by their relative lack of response to therapy with levodopa/carbidopa.

Parkinsonism + vertical gaze palsy = supranuclear palsy Parkinsonism + prominent ataxia = olivopontocerebellar  atrophy

Parkinsonism + prominent orthostatic hypotension = Shy-Drager syndrome (now called multiple-system atrophy)

Several other diseases can imitate Parkinsonism. Severe depression can cause a paucity of spontaneous movement that can mimic Parkinsonism.   Essential tremor can be mistaken   for the tremor of Parkinson disease, but the lack of other neurologic symptoms and a posi- tive family history of tremor and its amelioration with alcohol distinguish the two entities.   A normal pressure hydrocephalus can present with ataxia and gait disturbances, which can also be mistaken for Parkinson disease. The presence of dementia and urinary incontinence with dilated ventricles on a CT scan of the head can help identify this disorder. Huntington disease can present with akinesia and chorea. The positive family history and dementia usu- ally suggest the correct diagnosis.

Diagnosis. The diagnosis of Parkinson disease is a clinical one. It is important to identify any secondary causes of a patient’s Parkinsonism that are potentially reversible. There is no diagnostic test of choice that can identify patients with Parkinson disease.

Treatment. There are many medications available for the treatment of Parkinson disease. The underlying pathophysiology that causes Parkinson disease is the imbalance of dopaminergic (too little) and cholinergic (too much) tone on the basal ganglia. Thus, medical treatment revolves around increasing dopaminergic tone or decreasing cholinergic tone on the basal ganglia.

Not surprisingly, the medications available for the medical treatment of Parkinson disease directly stimulate dopamine receptors (carbidopa/levodopa, dopamine agonists), indirectly increase the amount of dopamine available (COMT inhibitors, selegiline, amantadine), or block acetylcholine stimulation of the basal ganglia (benztropine, trihexyphenidyl).

Direct-acting dopamine agonists such as pramipexole or ropinirole can be used alone as ini- tial therapy or in combination with small doses of levodopa/carbidopa. Two other dopamine agonists are bromocriptine and cabergoline. All of them are less efficacious than levodopa. Dopamine agonists do, however, have less dyskinetic side effects. Bromocriptine and per- golide are ergot derivatives and can cause cardiac toxicity.

The first step when considering what medication to start with is evaluating the patient’s func- tional status. Patients with an intact functional status are managed differently from patients with a compromised functional status.

Patients with intact functional status (less bradykinesia) are not generally given carbidopa/ levodopa as initial therapy. Such patients are started on anticholinergic medication when they are age <60. This is particularly true for those in whom tremor is the predominant symp- tom. When age >60, the treatment of choice is amantadine. The reason why anticholinergics are relatively contraindicated in elderly patients is because the side effects (dry mouth, uri- nary retention, constipation, confusion/hallucinations) occur more frequently and severely. Anticholinergics such as benztropine and trihexyphenidyl are used mostly to relieve tremor and rigidity. Avoid with BPH and glaucoma.

For patients with compromised functional status (more significant bradykinesia), the best initial therapy is carbidopa/levodopa. Carbidopa inhibits extracerebral dopa-decarboxylase, allowing more of the levodopa to reach the central nervous system, where it is needed. Levodopa is the precursor to dopamine. Carbidopa protects the levodopa from breakdown  in the periphery, ensuring its secure delivery to the central nervous system. There are sev- eral late complications to carbidopa/levodopa therapy: Dyskinesia (abnormal movements), akathisia (restlessness), and “on-off” phenomena are all disconcerting to the patient. All of these late side effects are termed “response fluctuations” and can be managed by using a sustained release form of  carbidopa/levodopa, adding a dopamine agonist, selegiline, or   a COMT inhibitor, or restricting the main protein meal to the night. COMT inhibitors        are tolcapone and entacapone. They are always used in conjunction with levodopa to help reduce the dose or modify response fluctuations. COMT inhibitors have no effect alone;  they decrease the metabolism of the levodopa. They are an adjunct to the use of levodopa to reduce adverse effects.

Selegiline was once thought to slow the progression of the disease. Selegiline can be used in those with a declining or fluctuating response to levodopa. Selegiline offers mild symptom- atic benefit in early disease. Rasagiline is a newer version.

Surgery should only be considered for patients who cannot tolerate or respond adequately to medical therapy. The procedures usually performed are pallidotomy or thalamotomy. The placement of deep brain stimulators is also effective when placed in the globus pallidus or subthalamic nuclei. Surgical therapy is a last resort.

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HUNTINGTON DISEASE

HUNTINGTON  DISEASE

A 34-year-old man comes to the clinic for an evaluation of strange spontaneous movements that have been occurring lately. Recently, while sitting at a family dinner, the patient experienced uncontrolled grimacing with grunting. His father died at the age of 41 from “dementia.”

Definition. A genetic degenerative brain disorder.

Etiology. Huntington disease is caused by the presence of the HD gene located on chromo- some 4p. The gene contains a CAG trinucleotide repeat expansion that codes for a protein called huntingtin. The HD mutation leads to abnormal cleavage of the huntingtin protein, interfering with nuclear mechanisms, and causing cell death. The disease is inherited in an autosomal dominant fashion. Successive generations tend to have the disease occuring at an earlier age. This is called anticipation.

Clinical Presentation. The clinical hallmarks of the disease include chorea and behavioral disturbance. Onset is usually in the fourth or fifth decade and can begin with either chorea or behavioral change. The personality changes consist of irritability, anger, paranoia, or signs of depression. Antisocial behavior may develop. The chorea may begin as fidgeting that progresses to sudden movements of the trunk or limbs. Gait is poorly coordinated and has a choreic quality. Memory is usually preserved until late in the disease but lack of judgment, disinhibi- tion, and inattention are early manifestations. There is frequently an associated depression. Dementia becomes severe later in the disease.

Diagnosis. Diagnosis is made by genetically testing for the presence of the CAG trinucleotide DNA repeat expansion. There is a 50% chance of passing it on to children. CT scanning shows cerebral atrophy. Atrophy of the caudate nucleus is severe later.

Treatment. Tetrabenazine helps the movement disorder of Huntington disease but will not reverse or cure the underlying disease process. Death occurs 15–20 years after the diagnosis. Haloperidol or clozapine can be used to control behavioral changes.

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DEMENTIA

DEMENTIA:

A 67-year-old woman is brought to the clinic complaining of forgetfulness. She states that recently she has been forgetting common phone numbers and the name of her mailman, whom she has known for 25 years. Her past medical history is significant for hypertension, coronary artery disease, and high cholesterol. Her physical examination is unremarkable.

Definition. Cognitive function is measured by various mental functions, including mem- ory, concentration, language, praxis, visuospatial functioning, and executive functions. “Dementia” refers to loss of memory with impairment of any other cognitive function suf- ficient to interfere with social or occupational functioning.

Etiology. There are more than 100 identifiable causes of dementia in the elderly. Among the many reversible causes of dementia, you should consider hypothyroidism, vitamin B12 defi- ciency, hepatic or uremic encephalopathy, CNS vasculitis, syphilis, brain abscess, brain tumor

(primary or metastatic), medications (especially anticholinergics), obstructive sleep apnea, central sleep apnea, trauma, subdural hematoma, normal pressure hydrocephalus (NPH), and depression. Irreversible causes of dementia include progressive multifocal leukoencephalopa- thy, Alzheimer disease, dementia with Lewy bodies, frontotemporal degeneration including Pick disease, vascular dementia including multi-infarct dementia and Binswanger disease, and Creutzfeldt-Jakob disease (CJD). Alzheimer disease accounts for 60 to 80% of all causes.

The prevalence of dementia is 1–5% between ages 65–69, rising to 45% by age 100. Only 5% of Alzheimer disease is inherited.

Clinical Presentation. The most common cause of dementia is Alzheimer disease. Typically, patients will present with problems in memory and visuospatial abilities that generally occur early in the course of the disease. Social graces can be retained despite significant loss of cognitive decline. Hallucinations and personality changes typically occur late in the course of the disease.

Mild cognitive impairment refers to memory loss without dysfunction of other cognitive domains. These patients have a higher risk of developing Alzheimer disease later in life but do not have Alzheimer disease. The rate of progression is 15–20% per year.

Alzheimer disease is, by definition, the loss of memory as well as other cognitive disturbances, such as aphasia, agnosia (the failure to identify entities despite intact sensory function), apraxia, or the loss of the ability to make plans and execute them. There is no single diagnostic test for Alzheimer disease.

Patients with frontotemporal dementias such as Pick disease will typically present with per- sonality changes early in the course of their disease, with relative sparing of their visuospatial function. Social, interpersonal, and emotional abnormalities precede memory impairment. Frontotemporal dementia is often noted primarily by the family because the patient lacks insight into their condition. There is no proven therapy for this condition.

Dementia with Lewy bodies (DLB) can be confused with delirium and is characterized by

fluctuating cognitive impairment.

Dementia secondary to Parkinson disease should be accompanied by clinical findings consis- tent with that disease. Recurrent visual hallucinations are also characteristic.

Dementia secondary to CJD is characterized by a shorter (weeks to months), more aggressive course than Alzheimer disease. Patients with CJD will present with dementia and myoclonus. Variant CJD is bovine spongiform encephalopathy (BSE). BSE is from the ingestion of prions from affected cattle. The diagnosis of CJD is by rapidly progressive dementia, myoclonus, ataxia, and the presence of 14-3-3 protein in the CSF. EEG may also help diagnose. These criteria can eliminate the need for brain biopsy.

Vascular dementia is divided into multi-infarct dementia, which typically has a stepwise pro- gression associated with discrete cerebrovascular events, and Binswanger disease, involving the subcortical white matter, which presents with a slowly progressive course.

Normal pressure hydrocephalus will present with prominent gait abnormalities early in the course of the disease that usually precede the onset of cognitive impairment. There will also be associated urinary incontinence.

Diagnosis. All patients with cognitive impairment should be assessed with a Mini Mental Status Examination (MMSE) to identify the areas of cognitive impairment.

Initially, the workup should focus on ruling out reversible causes of the dementia. If a revers- ible cause is identified, it should be treated, with the hope that cognitive function can be recovered. Laboratory studies should include a complete blood count (CBC), electrolytes, calcium, creatinine, liver function studies, glucose, thyroid-stimulating hormone (TSH), vitamin B12, RPR, and HIV.

Brain imaging is most useful for patients who have a focal neurologic exam, seizures, gait abnormalities, and an acute or subacute onset of their symptoms. EEG and CSF evaluation are not necessary except for NPH-opening pressure. No CSF marker is proven beneficial with the exception of 14-3-3 protein in CJD.

Treatment. Treatment of dementia revolves around insuring that the family and the patient have the proper medical and emotional support to cope with the disease. Caregivers are at an increased risk for depression and anxiety. Their concerns and frustrations should be addressed at frequent intervals.

Raising the level of acetylcholine in CSF benefits patients with Alzheimer disease. Pharmacotherapy with donepezil has been shown to improve cognitive function in mild to moderate dementia. Other anticholinesterase inhibitors (rivastigmine, galantamine) appear  to have similar efficacy.

Memantine is a disease-modifying drug used in advanced disease either alone or with a cholinesterase inhibitor. Memantine seems to be neuroprotective and reduces the rate of progression of disease.

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MULTIPLE SCLEROSIS

MULTIPLE SCLEROSIS

A 32-year-old woman comes to the emergency department complaining of numbness and tingling in her right hand. Her symptoms began several days ago and have worsened over the last several hours. She states that 3 years ago she had an episode of “seeing double” that lasted 2 days and resolved on its own. Physical examination is significant for hyperreactive reflexes bilaterally in her lower extremities. Increased spasticity is also noted in her lower extremities.

Definition. An autoimmune inflammatory disease of the CNS white matter characterized by a relapsing or progressive course.

Etiology. The cause of multiple sclerosis (MS) is thought to be multifactorial. There is evidence that genetic susceptibility plays an important role. The disease occurs primarily in female pop- ulations of Northern European descent and of child-bearing age, respectively. This implies a role for some sort of environmental trigger (infectious, dietary, climatic). Pathologically, focal areas of demyelination are characteristic of the disease.

Clinical Presentation. Commonly, patients will present complaining of weakness, numbness, tingling, or unsteadiness of a limb. Urinary urgency or retention, blurry vision, and double vision are all common initial manifestations of the disease. Symptoms may persist for several weeks or may resolve spontaneously over a few days.

There are several forms of  the disease that may change the course of  management and    are therefore important to recognize. Most patients will have a months-long to years-long disease-free period after their first exacerbation.

• Relapsing remitting disease: progression is characterized by relapses of active dis- ease with incomplete recovery during the periods of remission

• Secondary progressive disease: progression becomes more aggressive so that a con- sistent worsening of function occurs

• Primary progressive disease: symptoms are progressive from the onset of disease with the early onset of disability (least common form)

It is important to understand when the diagnosis of multiple sclerosis should be suspected. Classically, the diagnosis is made clinically when a young patient (usually age <55) presents with a history of multiple neurologic complaints that cannot be explained by the presence of one CNS lesion. In other words, suspect the diagnosis when a patient presents with multiple neurologic deficits separated by time and space (anatomy).

A number of triggers are known to exacerbate the disease. Infections  or  trauma  may acutely worsen the disease. Pregnancy, especially the 2 to 3 months following birth, may also exacerbate symptoms. However, there are generally fewer attacks during the pregnancy. Uncomplicated MS typically has no adverse effects on the outcome of the pregnancy.

Diagnosis. To diagnose MS you have to rely on clinical criteria supplemented with radiologic and laboratory confirmations. The advent of MRI scanning of the brain has dramatically changed the methods by which multiple sclerosis is diagnosed.

MRI of the brain is the most accurate test to diagnose MS, reaching a sensitivity of 85 to 95% in symptomatic persons. Increased T2 and decreased T1 intensity represent the increased

water content of demyelinated plaques in the cerebrum and spine. Enhancement of lesions with gadolinium indicates active MS lesions that may enhance for up to 2 to 6 weeks after an exacerbation. MS is an unusual disease in that the best initial test for the diagnosis is also the most sensitive one, namely MRI of the brain and spine.

Evoked response potentials detect slow or abnormal conduction in response to visual, audi- tory, or somatosensory stimuli. The limitation of this test for the diagnosis of MS is that many other neurologic diseases can give an abnormal result. The test is not specific for the diagnosis of MS. As a result, evoked potentials are rarely used to make the diagnosis.

Cerebrospinal fluid (CSF) analysis usually reveals a mild pleocytosis (usually <50 cells/L) and a total protein that is mildly elevated. A protein level exceeding 100 mg/dL is unusual and should be considered as evidence against the diagnosis of MS. An elevated IgG index (oligo- clonal bands) is found in 70 to 90% of patients with MS. The finding is nonspecific, and as a result, CSF for oligoclonal banding is recommended only when the MRI is nonconfirmatory but clinical suspicion for MS remains high.

Treatment. The treatment of multiple sclerosis can be divided into disease-modifying therapy, treatment of complications, and treatment for symptomatic relief during an acute exacerba- tion. The specific agents used depend on progression of the disease at the time of diagnosis.

In relapsing-remitting disease, there are 3 disease-modifying agents that have been shown to reduce the number of clinical exacerbations and the number of MRI lesions:

• Interferon-1a

• Interferon-1b

• Glatiramer acetate

More importantly, these medications seem to delay the onset of significant disability. Glatiramer is also known as copolymer I.

In secondary progressive disease, interferon-1b and mitoxantrone have been shown to reduce the number of exacerbations, decrease MRI activity, and delay onset of disability. In patients who receive mitoxantrone, dose-related cardiotoxicity is a concern; mitoxantrone should be given only to patients with a normal ejection fraction. Mitoxantrone is not a first-line agent to prevent disease progression because of its cardiotoxicity. In patients with relapsing-remitting disease or secondary progressive disease who cannot tolerate treatment with IFN-1b, IFN-1a, or glatiramer acetate, you can consider treatment with methotrex- ate, mitoxantrone, cyclophosphamide, intravenous immunoglobulin, or azathioprine. ACTH is no longer used.

No approved disease-modifying therapy exists at this time for primary progressive disease. Mitoxantrone, cyclophosphamide, and natalizumab are not used for a first episode of disease.

Natalizumab is associated with progressive multifocal leukoencephalopathy (PML).

The length and intensity of an acute exacerbation is shortened by the administration of gluco- corticoids. Typically, an acute exacerbation is treated with 3 days of intense intravenous steroids followed by a course of oral medication tapered over 4 weeks. In patients with severe disease who are unresponsive to steroid therapy, plasma exchange can be used as an alternative treatment.

For patients with spasticity, baclofen is the most effective medication. Tizanidine and diaz- epam are useful for nocturnal spasticity but are limited in their use for daytime symptoms because they cause intense somnolence. Pain secondary to trigeminal neuralgia and dys- esthesias  responds  well  to  carbamazepine, gabapentin, phenytoin, pregabalin, or  tricyclic

antidepressants. Bladder hyperactivity is treated with oxybutynin, whereas urinary retention is treated with bethanechol. Fatigue may be treated with amantadine or fluoxetine. Erectile dysfunction can be treated with sildenafil acetate.

All disease-modifying therapies are relatively contraindicated in pregnancy. Interferon and glatiramer should both be stopped for a pregnancy.

Fingolimod is an oral disease-modifying medication that decreases rates of MRI progression. It prevents lymphocytes from proliferating outside of lymph nodes. Cardiac toxicity can be severe.

Dalfampridine is an oral disease-modifying medication that increases walking speed. It       is a unique potassium channel blocker for which the precise mechanism of action (for improved walking speed) is not clearly  known.

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AMYOTROPHICLATERAL SCLEROSIS

AMYOTROPHICLATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is an idiopathic disorder of both upper and lower motor neurons. ALS has a unique presentation of muscle weakness combined with signs of upper motor neuron loss, cranial nerve palsies, respiratory involvement, and lower motor neu-   ron destruction, while at the same time preserving bowel, bladder sensory, cognitive, and sexual function. The cranial nerve, or bulbar, palsies result in dysphagia, difficulty chewing, decreased gag reflex, dysarthria (difficulty in articulating words), and difficulty in handling saliva. Since there is often respiratory muscle involvement, recurrent aspiration pneumonia is the most common cause of death. A weak cough is also characteristic, and this only worsens the respiratory problem.

There is no pain from abnormal sensory neuropathy because this is entirely a motor neuron disease. On the other hand, the upper motor neuron involvement gives significant spasticity that can lead to pain. Mentation, bowel, bladder, and sexual function remain intact for the same reason. In other words, a fully mentally alert patient loses nearly all motor control while still being able to think and perceive. The patient becomes fully aware of being trapped in a body that does not function. Head ptosis occurs because the extensor muscles of the neck become too weak to keep the head up.

Upper motor neuron manifestations are weakness with spasticity and hyperreflexia. Lower motor neuron manifestations are weakness with muscle wasting, atrophy, and fasciculations; this includes tongue atrophy. The combination of upper and lower motor neuron weakness is the unique presentation of ALS. The most accurate confirmatory test is the electromyogram, which will show diffuse axonal disease. CPK levels are sometimes mildly elevated, and the cerebrospinal fluid and MRI scans are normal.

The only treatment that may slow down the progression of  the disease is riluzole, which     is thought to work by inhibiting glutamate release. Death typically results in 3–5 years. Spasticity is treated with baclofen and tizanidine.

Many of the exam questions regarding ALS will be ethical questions on issues of the with- holding of care. Since ALS has no impact on cognitive function, the patient is felt to retain the capacity to make medical decisions. This means the patient has the right to refuse potentially lifesaving therapy such as antibiotics, nasogastric tube placement, tracheostomy, or the use of mechanical ventilation. The patient should not be allowed to commit suicide nor should the physician assist with the suicide. Withholding intubation or antibiotics is not considered assisting a suicide. Every adult patient with the capacity to understand the implications of their choice is allowed to refuse any therapy they do not want.

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MYASTHENIA GRAVIS

MYASTHENIA GRAVIS

A 35-year-old woman comes to the clinic complaining of double vision that seems to worsen near the end of the day. She also complains of difficulty chewing meat and other hard foods. She notices that her symptoms improve following a good night’s sleep. On neurologic examination, you note a snarling appearance when the patient is asked to smile, and a nasal tone is heard in her voice. You also note a weakness in the upper extremities when the patient is asked to clench her fist around your finger repeatedly.

Definition. Myasthenia gravis (MG) is a disease of the neuromuscular junction characterized by weakness and fatigability.

Etiology. In myasthenia gravis, an autoimmune process characterized by acetylcholine-recep- tor antibodies leads to a decreased number of active and functional acetylcholine receptors  at the postsynaptic  membrane.

Clinical Presentation. The major features in a patient’s history that help to diagnose myasthe- nia gravis are muscle weakness and fatigability. Initially, patients will complain of diplopia, ptosis, and difficulty swallowing. Speech may have a “mushy” or nasal quality and facial weak- ness may manifest as a“snarling” appearance when smiling. As the disease progresses, weakness may become generalized, involving proximal muscles in an asymmetric pattern. Deep tendon reflexes are intact. Pupillary responses are normal. There are no sensory abnormalities. Very severe disease may affect the muscles of respiration.

Eaton-Lambert myasthenic syndrome is characterized by increasing muscle strength on repetitive contraction. This syndrome is seen in association with malignancy, especially small-cell carcinoma of the lung.

Botulism may cause a myasthenic-like illness, but the pupils are usually dilated and repetitive nerve stimulation (on EMG) shows an incremental increase in muscular fiber contraction (opposite of myasthenia gravis).

Diagnosis. The best initial test for the diagnosis of myasthenia gravis is the acetylcholine-recep- tor antibody test. In generalized myasthenia gravis, 80–90% of patients will have a positive test. In the presence of fatigable muscle weakness, a positive antibody test is specific and virtually diagnostic. Antibodies are present in only 70% of those with disease limited to the eyes.

The edrophonium (Tensilon) test is sensitive but not specific for the diagnosis. Additionally, patients may experience nausea, diarrhea, fasciculations, syncope (rare), or bradycardia dur- ing the test, which are cholinergic symptoms.

Imaging studies of the chest such as x-rays and CT scan should be performed to detect a thymoma. Thymoma is found in 10–15% of patients. Thymic hyperplasia is found in 65%.

The most accurate test for the diagnosis of myasthenia gravis is electromyography (EMG). The characteristic finding is a decremental decrease in muscle fiber contraction on repetitive nerve stimulation.

Treatment. Anticholinesterase (usually pyridostigmine or neostigmine) medications are useful for the symptomatic treatment of myasthenia gravis. Pyridostigmine is longer lasting. If treatment with anticholinesterase medications is unsuccessful in providing symptomatic relief, the physician should consider immunosuppressive therapy.

There are numerous medications used for immunosuppressive therapy. These interventions primarily differ in the onset of therapeutic benefit. They are used if thymectomy is not effective.

Glucocorticoids are effective in improving weakness but take 1 to 3 months for you to observe a clinical benefit. Steroids are the initial immunosuppressive of choice. If patients fail steroid therapy, azathioprine is the most widely used medication used in combination with steroids. The benefits of azathioprine therapy may take more than 3 to 6 months to peak. Cyclosporine and cyclophosphamide are alternatives to azothiaprine but are more  toxic.

Plasmapheresis and intravenous immunoglobulin are immunosuppressive therapies noted for their ability to rapidly improve weakness in myasthenia gravis. They are therefore reserved for patients in acute myasthenic crisis. These therapies are used when respiratory involvement occurs or when patients go to the operating room.

Thymectomy is indicated in postpubertal patients and in those younger than 60 years of   age with generalized myasthenia gravis before initiation of immunosuppressive therapy.  Thymectomy is performed in those not controlled with anticholinesterase medications to prevent the use of potentially toxic medication such as systemic steroids. Thymectomies are also performed when a thymoma is present to prevent the spread of malignant thymic disease.

Aminoglycoside antibiotics may exacerbate myasthenia gravis and should be avoided. In fact, many medications may worse myasthenia gravis.

Mycophenolate is a newer immunosuppressive drug with less adverse effects than steroids or cyclophosphamide.

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GUILLAIN-BARRÉ SYNDROME (GBS)

GUILLAIN-BARRÉ SYNDROME (GBS)

A 46-year-old man is brought to your office complaining of “rubbery legs.” The patient states that his symptoms began 2 days ago and that approximately 3 weeks ago, he experienced several episodes of diarrhea, which resolved spontaneously. On neurologic examination, bilateral lower-extremity weakness and a loss of reflexes are noted.

Definition. An acute, often severe polyradiculopathy whose underlying pathophysiology is an autoimmune destruction of  myelin.

Etiology. Evidence suggests that GBS is caused by a misdirection of the immune response, where the body’s immune system attacks self-antigens mistaken for foreign antigens (molecu- lar mimicry).

Clinical Presentation. Most patients will present with rapidly developing weakness that typi- cally begins in the lower extremities and moves upward. On physical examination the patient is noted to lack reflexes in the muscle groups affected. The progression of the symptoms will develop over the course of hours to days. The legs are usually more affected than the arms and face. Fever, constitutional symptoms, or bladder dysfunction are rare and should raise the possibilities of alternate diagnoses.

In addition to the motor weakness, patients will typically complain of sensory disturbances that can take the form of pain or tingling dysesthesia. Sensory changes are due to loss of large sensory fibers, producing loss of reflexes and proprioception. Autonomic instability (profuse sweating, postural hypotension, labile blood pressure, cardiac dysrhythmias) occurs in severe GBS, requiring patient treatment in an intensive care unit.

Approximately 75% of patients who present with GBS will have a history of an infection    1 to 3 weeks preceding the onset of symptoms.  The infection is typically in the respira-  tory or gastrointestinal systems (Campylobacter jejuni), although GBS may be preceded by infections with human herpesvirus, cytomegalovirus, or the Epstein-Barr virus. The only association between immunizations and GBS occurred in 1976 with the introduction of the swine influenza vaccine. More recent formulations of influenza vaccine are associated with one case of GBS per million patients immunized. GBS occurs more frequently in patients with HIV, systemic lupus erythematous, and  lymphoma.

Diagnosis. Diagnosis lies principally in recognizing the typical pattern of weakness with the absence of reflexes, fever, and constitutional symptoms. A lumbar puncture for protein and cell count is always the best initial test. The characteristic finding is an elevated protein without an associate rise in the cell count on CSF. These changes in the cerebral spinal fluid do not occur until 48 hours after the onset of symptoms. The most accurate test for the diagnosis is electro- myography (EMG). EMG is used to detect evidence of demyelination of the peripheral nerves.

Treatment. Treatment should be initiated as quickly as possible because available therapy becomes ineffective approximately 2 weeks after the onset of symptoms.

Intravenous immunoglobulin and plasmapheresis are equally effective treatments.   There    is no benefit to combination therapy. Glucocorticoids are not effective in the treatment of acute GBS. Also, it is extremely important to monitor the vital capacity in patients with GBS and initiate early respiratory support to prevent death from respiratory  failure.

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Trigeminal Neuralgia

Trigeminal Neuralgia

Also known as tic douloureux, trigeminal neuralgia is an idiopathic pain syndrome resulting in sudden, severe, sharp pain starting near the side of the mouth and progressing to the ear, eye, or nostril. Attacks can be triggered by touch or movement such as talking or by eating. Trigeminal neuralgia can be so severe as to be nearly incapacitating. The pain lasts for a few seconds and disappears. Despite the pain, the sensory examination will be normal. Generally, trigeminal neuralgia is felt to be secondary to compression of the trigeminal nerve root by a blood vessel. Occasionally it can be a manifestation of multiple sclerosis or a posterior fossa tumor. With the exception of multiple sclerosis or the posterior fossa tumor, all imaging and neurologic testing will be normal.

Carbamazepine is the standard of care for treatment. In those not controlled with carbam- azepine, phenytoin, baclofen, or gabapentin can be tried. In those not responding to any form of medical therapy, surgery or radio-frequency lesioning into the affected nerve may work.

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Pseudotumor Cerebri

Pseudotumor Cerebri

Definition. An idiopathic increase in intracranial pressure also known as benign intracranial hypertension.

Etiology. The disorder is 8 to 10 times more common in women. There is an association with obesity, chronic lung disease, Addison disease, oral contraceptives, tetracycline use, and vitamin A toxicity. Often there is no identified cause and the disorder resolves spontaneously after several months.

Clinical Presentation. Patients present with a headache, visual disturbances such as diplopia, and sixth cranial nerve (abducens) palsy. Clinical findings include diplopia, papilledema, and enlargement of the blind spot on visual field testing. The CT and MRI are normal, and evalu- ation of cerebrospinal fluid is normal beyond an increase in pressure.

Treatment. Treatment consists of weight loss, removing offending agents such as oral con- traceptives, and the use of diuretics such as acetazolamide or furosemide. Steroids such as prednisone may help as well. In urgent cases, repeated lumbar punctures may help. If this is not effective and the disorder does not resolve, definitive treatment can be achieved with the placement of a surgical shunt between the ventricles and the  peritoneum.

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DISORDERS ASSOCIATED WITH HEADACHE

DISORDERS  ASSOCIATED  WITH HEADACHE

Headache

A 32-year-old woman comes to the office complaining of a headache that started 2 days ago. She locates her headache at the right side of her head and describes it as throbbing in quality. The headache is worsened by walking up stairs or around the block. She experiences nausea but denies vomiting. She also states that loud noise and bright light exacerbate her pain.

Definition. Headache is defined as pain located in the head, neck, or jaw.

Note

Any patient who presents with headache and the following should be considered to

have a secondary headache syndrome:

• “Worst headache of my life”

• Worsening symptoms over

days to weeks

• Abnormal neurologic exam

• Fever

• Vomiting preceding the

headache

• Headache induced by coughing, bending, lifting; or onset age >55

Etiology. There are many causes of headache that can be divided into primary or secondary headache syndromes. Primary headache syndromes include migraine, cluster, and tension headache. Secondary causes of headache include intracranial hemorrhage, brain tumor, meningitis, temporal arteritis, and glaucoma. Migrane affects 15% of the general population.

Clinical Presentation. The single most important question that has to be answered in any patient who presents complaining of a headache is whether there exists a serious underlying cause for the symptoms. By taking a thorough history and performing an adequate physical examination, it is possible to make this differentiation. An essential point in the history is to determine whether this is the first episode of headache that the patient has experienced. A his- tory of recurrent symptoms makes the diagnosis of a primary headache disorder more likely. A history of a first-time headache, especially when severe and rapidly peaking, speaks strongly for serious underlying pathology.

Headache with fever and nuchal rigidity suggests meningitis as the underlying cause. Conversely, a headache that is described as “the worst headache of my life” and/or “thunder- clap” at onset, and is accompanied by nuchal rigidity without fever, suggests an intracranial hemorrhage as the underlying cause. Patients with brain tumors will present complaining of headache that is described as a deep, dull, aching pain that disturbs sleep. The history of vomiting that precedes the onset of headache by a number of weeks, or a history of headache induced by coughing, lifting, or bending, is typical of posterior fossa brain tumors. Patients with temporal arteritis complain of a unilateral pounding headache associated with visual changes, described as dull and boring with superimposed lancinating pain. Patients will also complain of polymyalgia rheumatica, jaw claudication, fever, weight loss, and scalp tender- ness (difficulty combing hair or lying on a pillow). The scalp tenderness is from pain over the temporal artery. Temporal arteritis is a disorder of the elderly, generally presenting in patients age >50. Temporal arteritis gives an elevated sedimentation rate and is diagnosed with biopsy of the temporal artery. Do not wait for the biopsy results to initiate therapy with steroids. Patients with glaucoma will usually give a history of eye pain preceding the onset of the headache.

Once serious underlying pathology is excluded by history and physical examination, primary headache syndromes should be considered. The main primary headache syndromes are migraine, cluster, and tension headache.

 Migraine headaches are defined as a benign and recurrent syndrome of headache, nausea/ vomiting, and other varying neurologic dysfunctions. Patients will describe the headache    as pulsatile, throbbing, unilateral, and aggravated by minor movement. Other associated features include photophobia, phonophobia, and the time to maximal pain (4 to 72 hours). Migraine is a likely diagnosis when a typical trigger can be identified. Typical triggers include alcohol, certain foods (such as chocolate, various cheeses, monosodium glutamate), hunger, or irregular sleep patterns.

• Migraine without aura is a migraine without a preceding focal neurologic deficit.

• Migraine with aura (classic migraine) is a migraine accompanied by a preceding aura that consists of motor, sensory, or visual symptoms. Focal neurologic symp- toms usually occur during the headache rather than as a prodrome. The pathogno- monic aura for classic migraine is the scintillating scotoma. Only 20% of migraine headaches are accompanied by an aura. Visual auras are also described as stars, sparks, and flashes of light. Migraine equivalent is defined as focal neurologic symp- toms without the classic complaints of headache, nausea, and vomiting.

• Complicated migraine is migraine with severe neurologic deficits which persist after

the resolution of pain.

• Basilar migraine is migraine associated with symptoms consistent with brain-stem

involvement (vertigo, diplopia, ataxia, or dysarthria).

Tension-type headaches are described as tight, band-like headaches that occur bilaterally. Patients may also describe their headache as “vise-like,” and these headaches may be associ- ated with tightness of the posterior neck muscles. Patients will describe their pain as one that builds slowly, and the pain may persist for several days with or without fluctuations. Movement will not generally exacerbate the headache.

Cluster headaches, common in men, begin without warning and are typically described as excruciating, unilateral, periorbital, and peaking in intensity within 5 minutes of onset. They are rarely described as pulsatile in nature. The attacks last from 30 minutes to 3 hours and occur 1–3× day for a 4-to-8-week period. Symptoms associated with cluster headaches include rhinorrhea, reddening of the eye, lacrimation, nasal stuffiness, nausea, and sensitivity to alcohol. Horner syndrome is sometimes found. Emotion and food rarely will trigger a cluster headache.

Diagnosis. Patients with severe, sudden onset of a first-time headache accompanied by strong evidence for an underlying cause on history or physical examination should have a CT scan of the head to rule out any secondary causes.

Treatment. Always begin with an attempt to identify probable triggers for the patient and to modify lifestyle by avoiding those triggers. Most patients will require pharmacotherapy as well.

Pharmacologic treatment for migraine headaches can be divided into management of an acute episode and prophylaxis. Initially, for a mild migraine—which is defined as headache in the absence of nausea or vomiting—NSAIDs may be used.

Acutely, abortive therapy consists of sumatriptan, which acts as a serotonin receptor agonist. Dihydroergotamine is the alternative to the triptans. Ergotamine can be used in combina- tion with caffeine. The triptans are contraindicated in patients with known cardiovascular disease, uncontrolled hypertension, or pregnancy. In addition to sumatriptan, there is almotriptan, naratriptan, zolmitriptan, and eletriptan. These medications can be given orally, intranasally, or even subcutaneously, depending on the severity of the headache. Alternatively, ergotamine can be given for acute abortive therapy. Dopamine antagonists

such as metoclopramide can be given acutely as oral formulations to aid in the absorption of other abortive medications. When given parenterally, dopamine antagonists can provide relief acutely for migraine headaches.

Prophylactic treatment for migraine therapy should be initiated when patients have acute migraine headaches >3–4/month. The best prophylactic medication is a beta blocker. Propranolol, valproic acid, and topiramate are all considered first-line therapy for migraine prophylaxis. Verapamil and tricyclics can also be used. These medications take 2 to 6 weeks to have an effect and can be discontinued gradually over 6 months once clinical stabilization has occurred. Methysergide is not used because of the serious side effects associated with prolonged use (valvular and retroperitoneal fibrosis). SSRIs such as sertraline and fluoxetine can also be used for prophylaxis.

Opioid analgesics are not routinely recommended for the treatment of migraine headaches because of the possibility of developing addiction. They are used only in patients with severe, infrequent migraines that are unresponsive to other therapy. Other therapies for migraine headaches are acetaminophen and NSAIDs such as ibuprofen.

Treatment for tension headaches consists of relaxation. Patients should be encouraged to find activities that are relaxing for them. Initial pharmacotherapy consists of acetaminophen and NSAIDs. If the headache remains refractory to these medications, a muscle relaxant can be added to the regimen.

Cluster headaches are treated with a triptan or 100% oxygen. Prophylaxis of cluster headaches is best done with a calcium channel blocker. Prednisone and lithium are sometimes used.

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VERTIGO AND DIZZINESS

VERTIGO  AND DIZZINESS

A 53-year-old woman is brought to the emergency department complaining of dizziness. She describes walking to her bathroom and experiencing a sudden feeling of nausea. She then vomited and fell to the floor. She was unable to get up but was able to call 911. The patient describes a feeling of the room “spinning” around her, even though she realizes she was not moving.

Definition. Vertigo is defined as a false sensation of movement, i.e., the sensation of move- ment in the absence of actual movement.

Etiology. Vertigo may be caused by Ménière disease, labyrinthitis, positional vertigo, trau- matic vertigo, perilymphatic fistula, and cervical vertigo. Other causes include vascular disease of the brain stem, arteriovenous malformations, brain tumor, multiple sclerosis, drug overdose, and vertebrobasilar migraine.

Clinical Presentation. With the dizzy patient, the first step in the evaluation is to determine the nature of the patient’s complaints. “Dizziness” is a nonspecific term that provides no meaningful information about what is occurring to the patient. Simply by taking a complete history, it is possible to determine whether the patient is experiencing vertigo or presyncope.

Patients who experience vertigo will describe a sensation of movement without actually mov- ing. Commonly, patients will describe their environment spinning around them. Sensations of tilting, swaying, or falling forward or backward are all consistent with vertigo. Acutely, these episodes are commonly associated with nausea and vomiting.

Patients who complain of presyncope will describe their symptoms as “lightheadedness” or “feeling like I’m going to black out.” Associated symptoms include generalized weakness, palpitations, and shortness of breath. It is essential to differentiate vertigo from presyncope because vertigo is usually a manifestation of neurologic disease, whereas presyncope is a car- dinal  manifestation  of  cardiovascular disease.

Once you are convinced by the history that the patient is indeed experiencing an episode of vertigo, the next diagnostic question you have to answer is whether the vertigo is secondary to peripheral or central vestibular disease. This distinction is important because the manage- ment will differ between peripheral and central vertigo.

Several points on history and physical examination will distinguish central from peripheral vertigo.

Ménière disease is characterized by tinnitus, hearing loss, and episodic vertigo. Each episode lasts 1 to 8 hours. The symptoms wax and wane as the endolymphatic pressure rises and falls. The two most common causes of Ménière disease are syphilis and head trauma.

Benign paroxysmal positional vertigo is a cause of peripheral vertigo that characteristically is exacerbated by head movement or change in head position. Typically, episodes will occur   in clusters that persist for several days. There will be a latency of several seconds after head movement before the onset of vertigo. The vertigo usually lasts 10 to 60 seconds.

Labyrinthitis presents with sudden onset of severe vertigo that lasts for several days with hearing loss and tinnitus. The disease frequently follows an upper respiratory tract infection.

Perilymphatic fistula is a form of peripheral vertigo related temporally to head trauma (blunt trauma to the ear, e.g., a slap to the ear) or extreme barotrauma during air flight, scuba div- ing, or vigorous Valsalva maneuver. Explosions deafen people.

Central vertigo is caused by any cerebellar or brain-stem tumor, bleed, or ischemia. Drug toxicity or overdoses are important causes of central vertigo. Also, in the young patient with unexplained central vertigo, consider multiple sclerosis.

Treatment. Symptomatic treatment for peripheral vertigo includes meclizine or, in severe cases, diazepam.

Ménière disease is treated with a low-salt diet and diuretics. In patients who fail medical therapy, you can consider surgical decompression.

Benign paroxysmal positional vertigo is treated with positional maneuvers that attempt to move the otolith out of the circular canals (e.g., Dix Hallpike and Barany maneuvers).

Vertigo secondary to labyrinthitis is treated symptomatically with meclizine and diazepam when the symptoms are severe. Steroids help labyrinthitis.

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SEIZURES AND EPILEPSY

SEIZURES AND EPILEPSY

A 29-year-old man is brought to the emergency department by ambulance after being found convulsing in his bedroom. The patient’s mother says that during the episode her son was unable to respond to her frantic cries, and she describes jerking movements that became more frequent and then stopped after approximately 1 minute. The mother says that he seemed tired and lethargic for at least 20 minutes after the episode. She then called the ambulance to bring her son to the hospital.

Definition. A seizure is a paroxysmal event due to abnormally discharging central nervous system (CNS) neurons. Epilepsy is defined as a condition of recurrent seizures due to a chronic underlying process.

Etiology. Seizures are caused by “VITAMINS”:

Vascular (stroke, bleed, arteriovenous malformation)

Infection (meningitis, abscess, encephalitis) Trauma (especially penetrating) Autoimmune (CNS vasculitis)

Metabolic (hyponatremia, hypocalcemia, hypomagnesemia, hypoglycemia, hypoxia, drug overdose/withdrawal)

Idiopathic Neoplasm pSychiatric

Clinical Presentation. A seizure is essentially a paroxysmal, involuntary event (associated with abnormal movement or change of consciousness or both). Characteristically, seizures are sudden in onset, with or without an aura. Patients often complain of disorientation, sleepi- ness, and aching muscles for minutes to hours after the event. Patients may also experience incontinence, tongue biting, and headache as a result of the seizure. It may be difficult at times to differentiate a seizure from syncope, and it is important to obtain a complete history from any individual who witnessed the event. Generally, patients with syncope will not complain of significant postictal symptoms. They will recover consciousness within several minutes of the event, and on physical exam will not have evidence of incontinence or tongue biting.

It is important to classify seizures according to their clinical features because this will deter- mine what medications will be used for treatment. Seizures can be classified as partial versus generalized and complex versus simple.

Partial seizures occur within discrete portions of the brain. The patient will often complain of involuntary jerking of a finger or hand. When consciousness is maintained for the dura- tion of the seizure, the seizure is termed a simple partial seizure. When there is a change in consciousness during the seizure, the seizure is termed a complex partial seizure. When a partial seizure progresses to a generalized seizure, it is called a partial seizure with secondary generalization. Typically, the seizure will begin focally and become generalized as the seizure activity involves both cerebral hemispheres.

Generalized seizures arise from both cerebral hemispheres spontaneously without any detect- able focal onset. Generalized tonic-clonic (grand mal) seizures are characterized by tonic contraction of muscles throughout the body followed by intermittent relaxation of various muscle groups (clonic phase). Absence seizures (petit mal) are more common in children than adults; they are characterized by sudden, brief loss of consciousness without loss of postural tone. Characteristically, the EEG will show a generalized, symmetric 3-Hz spike-and- wave discharge pattern. Atonic seizures are characterized by sudden loss of postural tone last- ing 1 to 2 seconds. Myoclonic seizures are characterized by sudden, brief muscle contraction.

Status epilepticus is defined as recurrent or continuous seizures (lasting at least 5–30 min).

Diagnosis. EEG is the test of choice for the diagnosis of epilepsy. The diagnosis of idiopathic seizures is made only after secondary precipitating factors have been ruled out. An abnormal EEG alone is not diagnostic of epilepsy. Approximately 2 to 18% of the population has an abnormal EEG. Always check serum electrolytes, glucose, toxicology, and arterial blood gas to rule out hypoxia as a cause of a patient’s seizure. CT scan or MRI of the head is usually indi- cated to rule out a structural lesion as the cause of seizure. Think of any seizure as a symptom, much like shortness of breath or chest pain, which has an extensive differential diagnosis. The evaluation of any seizing patient is to rule out reversible causes of seizure.

Treatment. The treatment of seizures can be divided into the acute management of the acutely seizing patient (status epilepticus) and the chronic management of the epileptic patient.

The first step in the treatment of any acutely seizing patient is to secure the airway, breath- ing, and circulation. Once an adequate airway is established, breathing is assured, and the patient is hemodynamically stable, the next step is to simultaneously evaluate and treat any precipitating causes of seizure. If a reversible cause is identified, treat aggressively. If the patient continues to seize, the following strategy is appropriate. The initial drug of choice    is lorazepam or diazepam, both of which are benzodiazepines. These medications work by potentiating GABA receptor function. If the patient continues to seize, add phenytoin or fosphenytoin, which inhibits sodium-dependent action potentials. CNS side effects of phe- nytoin include diplopia, dizziness, and ataxia. Systemic side effects include gum hyperplasia, lymphadenopathy, hirsutism, and rash. If the patient continues to seize add phenobarbital. Side effects include sedation, ataxia, and rash. If, despite all of the above therapy, the patient continues to seize, add midazolam or propofol.

In patients with first-time seizure, anticonvulsant therapy should be started only if the patient has an abnormal neurologic exam, presented with status epilepticus, has a strong family history of seizure, or has an abnormal EEG. Otherwise, first-time seizures are generally not treated with long-term anticonvulsant therapy.

There is no superior drug in pregnancy. Valproic acid is clearly more dangerous in pregnancy.

For primary generalized tonic-clonic seizures, valproic acid, phenytoin, lamotrigine, carba- mazepine, or levetiracetam can be used. Lamotrigine works by decreasing glutamate release. Side effects include Stevens-Johnson syndrome. Absence seizures are treated with etho- suximide as first-line therapy. If ethosuximide is not an answer choice, valproic acid is an acceptable option. For myoclonic and atonic seizures, valproic acid is the treatment of choice. Overall, there is no single antiepileptic drug that’s truly superior to the others—valproic acid, phenytoin, levetiracetam and carbamazepine are all nearly equal in efficacy.

Partial seizures, whether they are complex or simple, and whether or not they progress to secondary generalized seizures, are all treated the same. Carbamazepine and phenytoin are considered first-line therapy. Valproic acid and lamotrigine are considered acceptable alter- natives, as is levetiracetam. It is very difficult to determine when to stop therapy. Therapy may be stopped if the patient has been free of seizures for 2–3 years. Sleep-deprivation EEG may be done first to determine if the patient is at low risk of a recurrence. A normal sleep- deprivation EEG means there is a lower likelihood of seizures.

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