4th article Flashcards
A 61-year-old woman presented to her primary care physician with
- a 4-week history of progressive bilateral leg weakness, 2. bilateral leg pain, and
- difficulty walking.
The weakness was
symmetric, without exacerbating or ameliorating factors, and did not fluctuate during the course of the day.
The patient also reported
- depression,
- anxiety,
- memory problems, and
- intermittent headaches that had begun several months earlier
She had a
dry mouth but no difficulty swallowing.
Previously very active, she had become
homebound over a period of several months because of the leg weakness.
Weakness is a common symptom and can result from
dysfunction of either the central nervous system (brain or spinal cord) or the peripheral nervous system (anterior horn cell, nerve, neuromuscular junction, or muscle).
Bilateral symmetric weakness of the legs can also result from problems with either
the central or the peripheral nervous system.
A key question is whether the
arms are affected.
If the arms are spared,
a thoracic spinal cord lesion is most likely.
Peripheral nervous system dysfunction affecting the nerves, muscles, or neuromuscular junction can also cause
leg weakness; however, it is unusual for the diffuse processes that cause weakness in the muscles or neuromuscular junction to spare the arms.
The history of headaches, anxiety, depression, and memory difficulties in this patient indicates that the
brain is involved; because only rare midline brain lesions would affect the innervation of the legs bilaterally, these findings probably reflect a multifocal process.
Finally, dry mouth is nonspecific but can tie into
leg weakness in many ways — for example, through the myelopathy that may accompany
- Sjögren’s syndrome and the
- autonomic dysfunction of the Lambert–Eaton myasthenic syndrome.
The patient had a history of
breast cancer that had been diagnosed 20 years earlier.
Treatment included
lumpectomy and radiation therapy, and there had been no evidence of recurrence.
She also had
- gastroesophageal reflux disease,
- hypertension, and the
- irritable bowel syndrome.
Her medications included
aspirin, lisinopril, ranitidine, and paroxetine.
She had
smoked one pack of cigarettes daily for 45 years.
Her father had
chronic obstructive pulmonary disease,
her mother had
neuromyelitis optica,
one sibling had
scleroderma, and
another sibling had
head and neck cancer.
The history of
breast cancer puts the patient at risk for recurrence, which can take the form of parenchymal lesions in the brain and spinal cord or carcinomatous meningitis.
Her smoking history and family history of head and neck cancer put her
at risk for a new, smoking-related cancer.
Paraneoplastic syndromes, as well as primary or metastatic cancers, can affect
the central or peripheral nervous system.
Paraneoplastic antibodies produced by typically small tumors can target either
neuronal cell-surface and synaptic antigens or intracellular antigens, leading to neurologic dysfunction.
Breast cancer and lung cancer in particular have been associated with a
wide range of neurologic paraneoplastic syndromes.
The family history of neuromyelitis optica and scleroderma places the patient at risk for
autoimmune conditions, many of which, such as systemic lupus erythematosus and Sjögren’s syndrome, can be manifested as leg weakness.
The patient was
afebrile.
Her heart rate was
84 beats per minute, her blood pressure was 160/74 mm Hg, her respiratory rate was 12 breaths per minute, and her oxygen saturation was 97% while she was breathing ambient air.
She had moderate
weakness in hip flexion and in knee flexion and extension bilaterally.
Strength in the feet, ankles, hands, and arms was
normal.
Knee and ankle reflexes were
normal, and plantar reflexes were flexor bilaterally.
Sensation of light touch and vibratory sensation were
normal throughout her body.
Her casual gait was
normal, but she had difficulty with a tandem gait and difficulty standing on her heels or toes.
Cranial-nerve function was
normal
The pattern of symmetric, proximal weakness without
reflex or sensory abnormalities probably points to a problem at the level of the muscle or neuromuscular junction.
Inflammatory diseases of the muscles include
polymyositis, dermatomyositis, and inclusion-body myositis; however, the presence of autonomic dysfunction (i.e., dry mouth) and neuropsychiatric features would be atypical.
Because most muscle disorders lead to breakdown of the muscles, measurement of the
serum creatine kinase level would be useful.
Although myasthenia gravis is by far the most common neuromuscular-junction disorder, the absence of
oculobulbar features makes this diagnosis highly unlikely.
The combination of proximal muscle weakness, autonomic dysfunction, and absence of eye findings is most consistent with a diagnosis of the
Lambert–Eaton myasthenic syndrome.
In more than 90% of patients with this syndrome,
autonomic dysfunction develops during the course of the disease, usually within the first 3 months after symptom onset.
To further evaluate these possible diagnoses, the patient should be assessed for the presence of
fluctuation, or changes in muscle strength over time, which is a key discriminator between disorders of the muscles and disorders of the neuromuscular junction.
This can be tested by examining sustained power in an affected muscle over a period of
10 to 30 seconds or by observing changes in power after exercise of a limb.
Patients with myasthenia gravis may have fluctuation with
fatigability, whereas slight increases in strength can be seen in patients with the Lambert–Eaton myasthenic syndrome.
Electromyography and nerve-conduction studies can definitively
localize weakness to either the muscle or the neuromuscular junction and provide clues about the cause.
Repetitive-stimulation testing during nerve-conduction studies can be used to
classify disorders of the neuromuscular junction as presynaptic, in which facilitation is seen (e.g., the Lambert–Eaton myasthenic syndrome), or postsynaptic, in which a decremental response is seen (e.g., myasthenia gravis).
Laboratory analysis showed
- normal blood counts and
- normal serum chemical measurements.
- Creatine kinase and thyrotropin levels were normal.
Computed tomography (CT) of the head and magnetic resonance imaging (MRI) of the lumbosacral spine showed
no abnormalities.
The results of conventional nerve-conduction studies and needle-electromyographic examination were
normal.
However, on repeated stimulation of the left median, ulnar, and peroneal nerves, there was an
abnormal decrement (>10%) in the compound muscle action potential (CMAP) amplitude.
These results confirm a diffuse disorder of the
neuromuscular junction, affecting both the arms and the legs.
The decremental response suggests a
postsynaptic deficit. Myasthenia gravis is the most common cause; the presence of elevated acetylcholine-receptor autoantibody titers would be confirmatory.
However, the symptoms and signs remain atypical of myasthenia gravis, because there are
no ocular or oropharyngeal symptoms despite generalized weakness.
These features, coupled with a history of
dry mouth, are consistent with the Lambert–Eaton myasthenic syndrome, which can be associated with a decremental response on low-frequency repetitive stimulation and facilitation of the response only on high-frequency repetitive stimulation.
Myasthenia gravis was diagnosed
clinically, and treatment with pyridostigmine (60 mg three times daily) was started, but the patient had no improvement in symptoms.
A test for acetylcholine-receptor autoantibodies was
negative.
Chest CT showed moderate
centrilobular emphysema but no residual thymic tissue, masses, or lymphadenopathy.
During the following 2 months, her symptoms progressed, and she required a
- walker to ambulate.
- Arm weakness,
- difficulty eating without assistance, and
- increasing memory problems also developed.
She was referred to an academic medical center for further evaluation.
The lack of response to pyridostigmine and negative test for acetylcholine-receptor antibodies lead me once again to
question the presumptive diagnosis.
Although some adults with myasthenia gravis have negative tests for acetylcholine-receptor antibodies, they still
typically have a response to anticholinesterase medications and have prominent ocular symptoms.
The presentation and course of illness in this case are most consistent with the
Lambert–Eaton myasthenic syndrome.
Although exploring a separate central nervous system cause for the patient’s cognitive problems may be useful, it is most likely that she has
limbic encephalitis caused by an antibody-mediated autoimmune attack on the brain, which may occur in association with the Lambert–Eaton myasthenic syndrome.
The key next step is to repeat the
electrodiagnostic testing, the accuracy and interpretation of which are dependent on the expertise of the examiner.
Neurologic examination revealed
intact extraocular movements and normal facial sensation and symmetry.
In addition to proximal leg weakness,
moderate weakness in arm abduction and elbow flexion and extension were now present.
Arm and leg reflexes were
normal.
The Mini–Mental State Examination score was 25 out of 30, with missed points for
date, month, hospital, floor, and recall.
Electrodiagnostic studies were repeated at the left
median nerve.
Motor-nerve amplitudes were
reduced, with normal conduction velocities. Sensory nerve conduction velocities were normal.
Repetitive nerve stimulation revealed an
abnormal, 38% decrement in CMAP amplitude.
Immediately after 1 minute of exercise, the maximum CMAP amplitude
increased by 94%; 2 minutes after exercise, the decrement in CMAP amplitude was 37%.
The increment in CMAP amplitude on repetitive nerve stimulation after exercise is diagnostic of a
presynaptic neuromuscular-junction condition, and a diagnosis of the Lambert–Eaton myasthenic syndrome can now be made.
Voltage-gated calcium channel antibodies are detected in the majority of cases overall and are particularly
common in cases associated with cancer.
Cancer is diagnosed in about half of patients with the
Lambert–Eaton myasthenic syndrome but may not be recognized at the time of the patient’s initial presentation, because the onset of the Lambert–Eaton myasthenic syndrome often predates the detection of cancer.
The patient’s initial chest CT scan did not reveal lesions in the lungs or mediastinum.
Whole-body positron-emission tomography (PET) would be reasonable to determine
whether she has extrathoracic cancer.
The patient’s persistent cognitive symptoms may represent the
encephalopathy that is seen in a minority of cases of the Lambert–Eaton myasthenic syndrome.
Imaging of the brain is indicated to
rule out an unrelated disorder and to determine whether metastases are present.
MRI of the brain showed an
abnormal, nonenhancing, bright signal along both hippocampi on T2-weighted images, which was more pronounced on the right side and extended along the parahippocampal gyri (Fig. 1).
A paraneoplastic-autoantibody panel revealed
- antineuronal nuclear antibody type 1 (anti-Hu antibodies) at a titer of 1:1920 (negative titer, <0.02).
The P/Q-type voltage-gated calcium-channel antibody test confirms the diagnosis of the
Lambert–Eaton myasthenic syndrome in this context.
The brain MRI scan shows areas of
inflammation in the limbic structures that probably indicate an antibody-mediated attack leading to the encephalopathy.
Although many autoantibodies can cause paraneoplastic limbic encephalitis,
anti-Hu antibodies are commonly associated with this condition and occur most frequently in the context of small-cell lung cancer. Screening for an underlying cancer is therefore critical.
Whole-body PET–CT showed a right precarinal lymph node, 1.9 cm in diameter, with a
maximal standardized uptake value of 7.7 (normal value, <2.5) and a right hilar lymph node, 1 cm in diameter, with a maximal standardized uptake value of 2.6 (Fig. 2).
A focus of hypermetabolic activity 1.5 cm in diameter was seen in the
medial left temporal lobe of the brain, which corresponded to the abnormality seen on the brain MRI scan.
There were no other abnormalities of
glucose uptake.
Chest CT showed a nodule, 7 mm in diameter, in the
lower lobe of the right lung; there was no associated hypermetabolic activity.
These results are highly suggestive of
lung cancer, most likely small-cell carcinoma.
A definitive diagnosis should be made by analysis of a biopsy sample from one of the
hypermetabolic lymph nodes.
Transbronchial needle aspiration of the
right precarinal lymph node was performed.
Histologic examination revealed
small-to-medium-size cells with scant cytoplasm and nuclear molding.
Immunohistochemical analysis showed expression of
- CD56,
- chromogranin, and
- thyroid transcription factor 1 in tumor cells (Fig. 3); results for CD45, cytokeratin 8, and cytokeratin 34bE12 were negative.
Small-cell lung carcinoma leading to the
- Lambert–Eaton myasthenic syndrome and
2. anti-Hu antibody–associated paraneoplastic limbic encephalitis was diagnosed.
The patient began treatment with
- carboplatin,
- etoposide, and
- radiation therapy to the mediastinum.
At the 6-month follow-up visit, she reported
substantial improvement in her leg weakness and no longer required the use of a wheelchair.
However, she reported continued difficulty with
short-term memory.
MRI of the brain showed persistent changes consistent with
limbic encephalitis but no signs of metastasis.
A CT scan of the chest showed a reduction in the size of the
precarinal and right hilar lymph nodes.
Because of her persistent memory problems,
prophylactic brain irradiation was not performed.
The Lambert–Eaton myasthenic syndrome is an
uncommon disorder, with a prevalence of 3.4
cases per 1 million people.1 Other causes of proximal muscle weakness, such as myasthenia gravis and the idiopathic inflammatory myopathies (polymyositis, dermatomyositis, and inclusion-body myositis), are much more common, with prevalence estimates of 150 cases per 1 million and 100 to 200 cases per 1 million, respectively.2,3
Making the diagnosis of the Lambert–Eaton myasthenic syndrome can be challenging;
up to 21% of cases are initially misdiagnosed as myasthenia gravis.1
How, then, was the discussant (the second author) able to arrive at the correct diagnosis with seeming ease? The key was to carefully consider
all the available information in order to identify patterns that pointed to specific diagnoses and ruled out others.
For example, what pointed to the muscles or neuromuscular junction as the most likely primary site of dz?
the presence of proximal muscle weakness without sensory or reflex abnormalities pointed to the muscles or neuromuscular junction as the most likely primary sites of disease.
However, common features of myasthenia gravis, such as oculobulbar weakness, were absent, whereas
atypical features, such as dry mouth, headaches, and cognitive dysfunction, were prominent.
This led the discussant to consider processes that also involve
the autonomic nervous system and the brain, and a pattern that most closely resembled the Lambert–Eaton myasthenic syndrome began to emerge.
Diagnostic tests to confirm this diagnosis and to look for underlying cancer were conducted, including
whole-body PET–CT and nerve-conduction studies with repetitive-stimulation testing.
The Lambert–Eaton myasthenic syndrome results from
autoantibodies affecting P/Q-type voltage- gated calcium channels on the presynaptic membrane of the neuromuscular junction,4 whereas myasthenia gravis results from autoantibodies affecting postsynaptic acetylcholine receptors.
Accordingly, presynaptic and postsynaptic neuromuscular-junction disorders can be distinguished by
electrophysiological testing with high-frequency or postexercise stimulation.
The accuracy of the performance and interpretation of electrodiagnostic studies is dependent on the
expertise of the examiner,5 which may explain the different results of the initial and repeated studies in this case.
Overall, 50 to 60% of patients with the Lambert–Eaton myasthenic syndrome are found to have an associated
cancer — in most cases, small-cell lung cancer. Nonpulmonary cancers, such as prostate cancer, thymoma, and lymphoproliferative disorders, have also been associated with this syndrome.1,6
A task force of the European Federation of Neurological Societies recommends initial screening with a CT scan, followed by
PET imaging or combined PET–CT imaging if the initial CT scan is negative, with follow-up testing for at least 2 years for patients in whom the initial imaging studies are negative.7
These recommendations are largely based on data from case series showing a high sensitivity of chest CT for lung cancer (vs. the low sensitivity of chest radiography) among patients presenting with the
Lambert–Eaton myasthenic syndrome; among these patients, most cancers that were detected were identified on the initial chest CT scan, and 96% were identified in the first year.7,8
However, we lack evidence from randomized, controlled trials regarding the outcomes and cost-effectiveness of this and other cancer screening strategies in such patients. As was observed in this patient,
neurologic symptoms in patients with cancer-related Lambert–Eaton myasthenic syndrome often show marked improvement with treatment of the underlying cancer.9
In cases in which muscle weakness persists, adjunctive therapies such as
pyridostigmine, intravenous immune globulin, or 3,4-diaminopyridine may be considered,1 although the evidence for the effectiveness of these therapies is limited.10
Nonspecific symptoms such as
weakness can pose a diagnostic challenge for even the most astute clinicians, particularly when a rare disease is the underlying cause.
what 2 things should prompt reconsideration of the initial diagnosis?
The presence of atypical clinical features or a lack of response to standard therapies
