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Ovid: Fifty Neurologic Cases from Mayo Clinic

Editors: Noseworthy, John H. Title: Fifty Neurologic Cases from Mayo Clinic, 1st Edition Copyright ©2004 Oxford Unversity Press (Copyright 2004 by Mayo Foundation for Medical Education and Research) > Table of Contents > Case 9: Early satiety, syncope, and seizures Case 9: Early satiety, syncope, and seizures CASE 9 History A 59-year-old man developed paresthesias of both feet. This was followed within weeks by early satiety, postprandial vomiting of undigested food, and reduced frequency of bowel movements. He became completely unable to eat and lost 60 Ib. A J-tube was placed. He had a 40 packyear cigarette habit, but extensive studies for malignancy were negative. In the subsequent weeks, dry mouth, orthostatic hypotension, lower extremity loss of sweating, and impotence developed. Medical therapy failed to improve the gastrointestinal dysmotility. Eleven months into the illness, refractory simple partial and secondary generalized seizures developed, with postictal aphasia, headaches, short-term memory loss, depression, and night sweats. He was treated with plasma exchange and oral cyclophosphamide. His gastrointestinal symptoms improved markedly, and he was able to resume a normal diet. His seizures became easier to control. He was able to return to work part time on his farm. Examination The pupillary light reflex was normal. Other findings included a mild reduction in short-term memory and asymmetric loss of pin and temperature sensations in a stocking distribution. His feet were dry. Measurement of blood pressure with the patient standing revealed orthostatic hypotension. Investigations Autonomic studies documented orthostatic hypotension and a blunted heart rate response to a Valsalva maneuver. Sweating was reduced in the legs. Gastroparesis and delayed small-bowel transit time were demonstrated. At presentation, serum type 1 antineuronal nuclear autoantibody (ANNA-1) was detected (1:15, 360). Cranial magnetic resonance imaging (MRI) showed mild atrophy and increased fluid attenuation inversion recovery (FLAIR) signal in the left mesial temporal, insular, and opercular cortices (Figure). The results of an exploratory mediastinoscopy and a video-assisted thoracic surgery procedure were negative. Computed tomographic (CT) scans of the chest at 3-month intervals and positron emission tomographic (PET) scans were uninformative. Thirty months after the onset of symptoms, chest CT demonstrated a small lesion in the right upper lobe that remained stable for several months. Eight months later, this lesion had enlarged and a right upper lobectomy was performed. P.34

FIGURE. Coronal FLAIR magnetic resonance image demonstrating a nonenhancing signal abnormality in the left amygdala and inferior frontal cortex, with associated mesial temporal atrophy.

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DIAGNOSIS CASE 9 Paraneoplastic autonomic neuropathy and limbic encephalitis
Commentary by Dr. Steven Vernino Neurologic paraneoplastic syndromes are rare but severe neuroimmunologic complications of malignancy. The tumors most commonly associated with these syndromes are small cell lung carcinoma, ovarian carcinoma, breast carcinoma, and thymoma. At surgery, a 1.0 × 1.0 × 1.0-cm grade 3 (of 4) squamous cell carcinoma was identified. These syndromes usually have a subacute onset and a relentlessly progressive clinical course leading to profound morbidity. Typically, the neurologic presentation antedates the diagnosis of malignancy, and the cancer, when found, tends to be localized and responsive to treatment. Clinical manifestations can be quite varied and multifocal in the nervous system. Several distinct clinical syndromes are recognized, including sensory neuronopathy, cerebellar degeneration, limbic encephalitis, brainstem encephalitis, and opsoclonus-myoclonus. Many patients, however, have a combination of symptoms that do not fit neatly into a single syndromic classification. The MRI findings in this patient are typical of paraneoplastic limbic encephalitis. Extratemporal radiographic involvement, particularly of the insular cortex, is not uncommon. Paraneoplastic limbic encephalitis affects the mesial temporal lobe and mesial limbic structures (cingulate gyrus, orbitofrontal cortex, and mamillary bodies), resulting in the typical triad of memory impairment, temporal lobe seizures, and psychiatric symptoms (including dramatic personality changes, hallucinations, or depression). Small cell carcinoma of the lung is the most commonly associated neoplasm, but other types of cancer have been identified. Autonomic neuropathy can occur as a remote effect of malignancy, although paraneoplastic nerve disorders also manifest as sensorimotor neuropathy, polyradiculoneuropathy, or sensory neuronopathy. Paraneoplastic autonomic neuropathy can present as subacute severe pandysautonomia but more frequently takes the form of severe gastrointestinal dysmotility (gastroparesis or intestinal pseudo-obstruction). Pathologically, paraneoplastic dysmotility has been associated with an inflammatory destructive process affecting myenteric ganglia of the gut. Several neuronal autoantibodies have been reported as markers of paraneoplastic limbic encephalitis or paraneoplastic dysautonomia, including ANNA-1 (also known as “anti-Hu”), amphiphysin-IgG, collapsin response-mediator protein-5 (CRMP-5)-IgG, parietal cell anitbody-2 P.36
(PCA-2), ANNA-3, and “anti-Ma.” No clear pathogenic relation has been established between any of these specific antibodies and a particular neurologic syndrome. Despite a typical clinical course and the detection of small cell lung carcinoma, a small proportion of patients with paraneoplastic neurologic disorders lack any of the currently recognized autoantibody markers. Most of the autoantibodies are highly predictive of specific neoplasms. For example, small cell lung carcinoma is found in more than 80% of patients who are seropositive for ANNA-1. Seropositivity for ANNA-1 should prompt a careful evaluation for an underlying small cell lung carcinoma, even if routine imaging studies are negative. PET imaging of the chest is proving to be more sensitive than CT. Paraneoplastic neurologic symptoms usually precede the diagnosis of cancer, and, as in the case presented here, the diagnosis of malignancy may be delayed for many years. In some cases, a small focus of malignancy is found only at autopsy. Despite evidence of an autoimmune pathogenesis of these disorders, immunomodulatory treatment generally has been regarded as ineffective. Treatment of the underlying malignancy is considered the mainstay of treatment for these disorders. In some cases, immunomodulatory treatment with high doses of corticosteroids, plasma exchange, intravenous immunoglobulin, or conventional immunosuppressive agents (e.g., cyclophosphamide) offers a reasonable chance of arresting neurologic progression. Treatment is most likely to benefit patients who are not severely disabled, probably because they have less permanent neuronal loss and therefore a better substrate for rehabilitation and for restoration of function through plasticity. Patients without active malignancy need close oncologic follow-up because immunosuppressive treatment has the potential to impair immune surveillance for malignancy. The patient presented here received cyclophosphamide for 9 months and since then has had sustained clinical and radiographic improvement. He has residual memory deficit and requires anticonvulsant therapy. REFERENCE Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998;50:652-7.

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