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28-Year-Old Man With Severe Vertigo

      A 28-year-old Sudanese man presented with a 1-month history of dizziness. He reported illness that began with self-limited upper respiratory tract symptoms without fever, lasting about 2 days. The patient described the first episode as severe lack of balance secondary to a sensation of spinning dizziness while he was walking. This first episode lasted more than 20 minutes. He fell but did not lose consciousness or sustain any head trauma. He denied any preceding trauma, aura, fever, nausea, or headache. Episodes occurred with increasing frequency and were happening almost daily with activity or at rest. He recently visited the emergency department and was prescribed meclizine, which produced only minor improvement of his vertigo. The patient took no other medications. He had smoked 1 pack of cigarettes daily for 6 years but recently quit, and denied any relevant family history.
      On physical examination the patient was afebrile and in no acute distress. No nystagmus was present before provocative testing. He had rotary nystagmus during a right Dix-Hallpike maneuver as well as down-beating nystagmus after sitting up that persisted with a left rotatory component and did not fatigue for more than 20 seconds. Cranial nerve testing exposed no other abnormalities. The patient showed no photophobia. Muscle strength testing and sensitivity were normal. The patient had a slow, unsteady, wide-based gait and positive results with the Romberg test. Ataxia was seen bilaterally on finger-nose test. Brudzinski and Kernig signs were negative. No lymphadenopathy was detected, and sinus translumination was normal.
      • 1.
        At this point, which one of the following seems most likely to be causing these symptoms?
        • a.
          Multiple sclerosis
        • b.
          Episodic ataxia type 2
        • c.
          Meniere disease
        • d.
          Migrainous vertigo
        • e.
          Acute cerebellar disease
      The first question that should be asked when developing differential diagnoses for vertigo is as follows: Is this a central or peripheral defect? Helpful clinical features that characterize central vertigo include nystagmus that is purely vertical, horizontal, or rotatory and not inhibited by fixation. With central vertigo, the imbalance is more severe, the patient is sometimes unable to stand still, and hearing deficits are less common.
      Central vertigo occurs in approximately 20% of patients with multiple sclerosis. However, this symptom typically appears in patients with a previous diagnosis of the disease; this patient's ethnic background also is rare among patients with multiple sclerosis, making the diagnosis less likely. Episodic ataxia type 2 is characterized by attacks of severe vertigo, nausea, and vomiting beginning in childhood or early adult life. As in our patient, it can be progressive. Patients often develop persistent cerebellar symptoms and cerebellar atrophy. The patient's age puts this disease lower in the differential diagnosis. Meniere disease is a peripheral vestibular disorder attributed to excess endolymphatic fluid pressure leading to episodic inner ear dysfunction. The duration of symptoms along with the persistent nystagmus and cerebellar findings classify this patient as having central vertigo; therefore, Meniere disease is unlikely.
      • Derebery MJ
      The diagnosis and treatment of dizziness.
      Migrainous vertigo can have both central and peripheral vestibular manifestations. The mechanism by which a migraine causes vertigo is not understood. In their series of 91 cases, Cutrer and Baloh
      • Cutrer FM
      • Baloh RW
      Migraine-associated dizziness.
      documented a history of vertigo that they attributed to increasing circulating levels of neurotransmitters. This phenomenon could also explain the heightened sensitivity to motion sickness that was frequently documented. Because this patient had no history of migraine, migrainous vertigo is unlikely. Although cerebellar hemorrhage or infarction would be expected in an older patient, possible nonatherosclerotic causes of ischemia (ie, hemoglobulinopathy, traumatic dissection) should be considered. The ataxia present on examination was suggestive of a cerebellar etiology and, in addition to ischemia, a paraneoplastic disorder cannot be excluded at the moment, making acute cerebellar disease the most likely cause of symptoms.
      Because the patient presented with central vertigo, noncontrast brain magnetic resonance imaging (MRI) was performed; results were unremarkable. Laboratory testing yielded normal results for complete blood cell count, electrolytes, kidney function, and liver function. The sedimentation rate was mildly elevated at 28 mm/h (reference ranges given parenthetically) (0-25 mm/h).
      • 2.
        Which one of the following would be the most appropriate next diagnostic test?
        • a.
          Biopsies of the small intestine
        • b.
          Magnetic resonance angiography (MRA)
        • c.
          Transcranial Doppler ultrasonography
        • d.
          Lumbar puncture
        • e.
          Rotary chair testing
      The initial list of differential diagnoses for a patient with central vertigo is long and includes migrainous vertigo, basilar artery occlusion, transient ischemic attacks, acute cerebellar disease, cranial nerve deficits, multiple sclerosis, and episodic ataxia type 2. Central Whipple disease can also be considered because it can present with cerebellar ataxia along with myoclonus, hemiparesis, and peripheral neuropathy. Our patient showed no sign of cognitive impairment, a prominent feature of central Whipple disease; therefore, small intestine biopsies would not be helpful. If central Whipple is suspected, polymerase chain reaction with a cerebrospinal fluid sample would be a better test than biopsy of small intestine. Although intra-arterial angiography is normally used to diagnose occlusions in the vertebrobasilar system, MRA and transcranial Doppler ultrasonography are noninvasive options. The patient's age and lack of risk factors made it unlikely that he had cerebrovascular disease; thus, MRA or Doppler ultrasonography was unnecessary. Because other diagnoses are unlikely, it is important to evaluate patients for a neurologic paraneoplastic syndrome. A lumbar puncture, a test for central neurologic paraneoplastic syndromes, is the best modality.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      The rotary chair has been used primarily for analyzing horizontal canal vestibule ocular reflex. Traditionally, rotary chair testing has been used for 2 major purposes: to diagnose peripheral vestibular lesions and to monitor patients undergoing pharmacological vestibular ablation for Meniere disease. As our case is clinically compatible with central vertigo, this test would be unlikely to provide useful information.
      Results from lumbar puncture revealed the following: clear fluid with 35 total nucleated cells (0-5 cells/μL), of which 91% were lymphocytes (40%-80%), 6% were monocytes (25%-35%), and 3% were neutrophils (2%-4%). Immunoglobulin G index was 0.93 (<0.85); IgG was 14.70 mg/dL (<8.1 mg/dL), and total protein concentration was 86 mg/dL (14-45 mg/dL). IgG in serum was 1740 mg/dL (600-1500 mg/dL).
      Multiple sclerosis plaques were not visible on MRI, and the patient had no symptoms of infection; consequently, a neurologic paraneoplastic disorder was the most probable diagnosis.
      • 3.
        Which one of the following is the most likely cause of paraneoplastic syndrome in this patient?
        • a.
          Small cell lung cancer (SCLC)
        • b.
          Germ cell tumor of testis
        • c.
          Thyroid cancer
        • d.
          Breast cancer
        • e.
          Melanoma
      The best answer takes into account the frequency of cancer among male patients aged 25 to 29 years (according to the Surveillance Epidemiology and End Results database) cross-tabulated with the frequency of cancers associated with the patient's specific paraneoplastic syndrome.
      • National Cancer Institute
      SEER: Surveilance Epidemiology and End Results Web site.
      The patient's symptoms, physical examination findings, and laboratory results indicate he has paraneoplastic cerebellar degeneration (PCD).
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      • Shams'ili S
      • Grefkens J
      • de Leeuw B
      • et al.
      Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
      Lung cancer, specifically SCLC, is associated with PCD, but a young man's likelihood of having SCLC is less than 5%. On the other hand, germ cell testicular cancer and PCD are associated.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      • National Cancer Institute
      SEER: Surveilance Epidemiology and End Results Web site.
      • Dalmau J
      • Rosenfeld MR
      Paraneoplastic syndromes affecting brain and cranial nerves. Up to Date Web site. 2007.
      Testicular cancer is the most common solid tumor among young male patients, particularly those aged 15 to 35 years, so this is the most likely cause of the paraneoplastic syndrome in this patient. More than 10% of the cancers diagnosed in this age group are classified as endocrine malignancies; thyroid cancer is the most prevalent. However, thyroid malignancies are not associated with PCD.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      Male breast cancer is rare, representing 1% of all breast cancers and less than 1% of all cancers in men. The age distribution in women with breast cancer is bimodal with peaks at 52 and 71 years, whereas in men it is unimodal with a peak at age 71 years.
      • Kamila C
      • Jenny B
      • Per H
      • Jonas B
      How to treat male breast cancer [published online ahead of print November 4, 2007].
      Although PCD is associated with breast cancer, it is not the most likely neoplasm in this patient considering the rarity of the disease and the patient's age. Melanoma is certainly prevalent in young male patients (18% of all cancers), but it is not part of the differential diagnosis for his paraneoplastic syndrome.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      • National Cancer Institute
      SEER: Surveilance Epidemiology and End Results Web site.
      On further examination, we found bilateral undescended testicles. The patient had never had a general medical examination, and testicular examination is not part of the routine neurologic physical examination. Computed tomography of the chest, abdomen, and pelvis showed only a 3 × 2.3-cm nodular enlargement in the left seminal vesicle (Figure). Metastatic testicular tumor was considered. The voiding cystourethrogram showed a normal male urinary tract with no evidence of congenital abnormality, and semen analysis showed no evidence of sperm. The patient's karyotype revealed 46,XY. Because the testes were not producing sperm, bilateral orchiectomy was performed. After surgery, the pathology report confirmed not only a seminoma confined to the right testis but also intratubular germ cell neoplasia in the left testicle. Surgical margins were free of tumor, and serum α-fetoprotein,l-lactate dehydrogenase, and β human chorionic gonadotropin levels were normal.
      • 4.
        Which one of the following is the most appropriate treatment of this patient's paraneoplastic disorder?
        • a.
          Treatment of the underlying tumor
        • b.
          Intravenous immunoglobulin
        • c.
          Cyclophosphamide and methylprednisolone
        • d.
          Neurorehabilitation
        • e.
          Antiepileptic drugs
      Figure thumbnail gr1
      FIGUREContrast computed tomography of the chest, abdomen, and pelvis showed a 3 × 2.3-cm mass (arrow) that, on postoperative evaluation, was a malignancy in an undescended testicle.
      Increased survival in patients receiving antitumor treatment was demonstrated in a large series of patients with PCD. In our patient, treatment of the underlying tumor is the most appropriate approach. Survival from time of diagnosis was significantly worse in patients who presented with specific antibodies including anti-Yo and anti-Hu.
      • Shams'ili S
      • Grefkens J
      • de Leeuw B
      • et al.
      Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
      Keime-Guibert et al
      • Keime-Guibert F
      • Graus F
      • Fleury A
      • et al.
      Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone.
      studied the utility of intravenous immunoglobulins, cyclophosphamide, and methylprednisolone in patients with neurologic paraneoplastic syndrome. The results showed that vigorous immunosuppressive treatment does not benefit severely disabled patients. Although vigorous immunosuppressive treatment made stabilization possible for a few patients, especially those with sensory neuropathy, this observation deserves further evaluation. Neurorehabilitation using speech and swallowing therapy is especially important in patients with PCD, but it is not the primary treatment.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      Case reports suggest some improvement in symptoms with antiepileptic drugs and propanolol, but the primary means of therapy is to treat the underlying malignancy.
      In PCD, the cerebellar deficit usually stabilizes, but the patient is often severely incapacitated; most are confined to bed in the first 3 months after diagnosis. Our patient underwent orchiectomy for stage I pure seminoma. Radiation therapy administered after orchiectomy prevents relapse in more than 95% of patients with clinical stage I seminoma, but this effect does not improve survival. Observation and deferred treatment for only patients with recurring disease yields the same survival rate. However, because of the atypical presentation and the possibility of occult metastasis, this patient was given a total of 2250 cGy. A 5-day course of intravenous methylprednisolone followed by oral cyclophosphamide was added to the treatment of PCD.
      • 5.
        Which one of the following statements about this patient's disease is true?
        • a.
          Anti-Hu antibodies (type 1 antineuronal antibody) are most frequently associated with PCD
        • b.
          Patients are mainly young men
        • c.
          The most frequently PCD-associated tumor is adenocarcinoma of the lung
        • d.
          The absence of onconeural antibodies cannot rule out PCD
        • e.
          If appropriate tumor screen is negative, no follow-up is necessary
      When antibodies are found, anti-Yo antibodies (PCA-1), not anti-Hu antibodies, are most frequently associated with PCD. This syndrome usually presents in middle-aged women, with an average age of 61 years. The most frequently associated tumor is SCLC, in up to 60% of the reported cases of PCD. The absence of onconeural antibodies cannot rule out the possibility of PCD because only 50% of patients with PCD have detectable antibodies, making this the correct answer. Antibodies can be confirmatory and can point toward the underlying primary malignancy. In cases in which the initial tumor screen is negative, patients should also be followed up at regular intervals, such as every 6 months for up to 4 years. Screening should be especially aggressive among those who have positive antibodies.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      Our patient was evaluated 4 months after treatment and had improved substantially with fewer episodes of vertigo. The truncal ataxia in a sitting position and upper gaze nystagmus resolved completely. On downward and right gaze, only mild nystagmus persisted. A follow-up MRI showed no cerebellar atrophy.

      DISCUSSION

      Neurologic paraneoplastic disorders are not attributable to toxicity of cancer therapy, cerebrovascular disease, coagulopathy, infection, toxic or metabolic causes, or metastases. Despite being less common than nervous system metastases, paraneoplastic disorders are important because (1) they often cause severe and permanent neurologic morbidity, (2) they can be the presenting feature of an otherwise undiagnosed tumor, and (3) their early diagnosis increases the likelihood of successful tumor treatment.
      • Dropcho EJ
      Update on paraneoplastic syndromes.
      Precise criteria for diagnosis of paraneoplastic syndromes are available; however, it is important to exclude other known causes that could explain the neurologic syndrome even if onconeural antibodies are positive.
      • Graus F
      • Delattre JY
      • Antoine JC
      • et al.
      Recommended diagnostic criteria for paraneoplastic neurological syndromes.
      Paraneoplastic cerebellar degeneration is a heterogeneous group of disorders characterized by subacute cerebellar ataxia. Cerebellar signs usually begin with gait ataxia and, during a few weeks or months, progress to severe, truncal, and usually symmetric limb ataxia, with dysarthria and nystagmus.
      • Shams'ili S
      • Grefkens J
      • de Leeuw B
      • et al.
      Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
      • Peterson K
      • Rosenblum MK
      • Kotanides H
      • Posner JB
      Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients.
      Brain MRI studies are initially normal, but can demonstrate cerebellar atrophy in the latter stages of the disease. Diffuse increase of the T2 signal in the cerebellum can provide a useful diagnostic clue in the assessment of PCD.
      • Rupasinghe J
      • Butler E
      Progressive ataxic gait disorder.
      Cerebrospinal fluid examination shows inflammatory signs without malignant cells in about 60% of patients with PCD.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      Paraneoplastic syndromes depend on an autoimmune process triggered by cancer and directed against onconeural antigens common to both the cancer and the nervous system. The prognosis of patients with PCD is related to the presence of specific antibodies. Survival from time of diagnosis appears to be significantly worse in patients with anti-Yo and anti-Hu antibodies than in patients with anti-Tr and anti-Ri antibodies.
      • Shams'ili S
      • Grefkens J
      • de Leeuw B
      • et al.
      Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
      In general, the primary neoplasm determines the mortality.
      Clinical management of patients with known or suspected paraneoplastic syndromes includes 4 components: verification that the disorder is in fact paraneoplastic, identification of the associated tumor, treatment of the tumor, and suppression of the autoimmune effectors that cause neuronal injury.
      • Dropcho EJ
      Update on paraneoplastic syndromes.
      For identification of associated tumors, it is important to recognize the specific syndrome.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      As demonstrated by Shams'ili et al,
      • Shams'ili S
      • Grefkens J
      • de Leeuw B
      • et al.
      Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
      antitumor treatment is the most relevant factor in treating paraneoplastic syndromes.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      Although aggressive immunosuppressive treatment is not useful in patients who are already severely disabled by neurologic paraneoplastic syndromes, patients at the onset of treatment who are mildly to moderately affected might benefit from a transient stabilization of their symptoms using combinations of immunoglobulins, cyclophosphamide, and methylprednisolone.
      • Keime-Guibert F
      • Graus F
      • Fleury A
      • et al.
      Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone.
      Novel treatments of PCD, such as plasmapheresis and rituximab, have been evaluated; however, few data examine their utility.
      • Vedeler CA
      • Antoine JC
      • Giometto B
      • et al.
      Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.
      • Taniguchi Y
      • Tanji C
      • Kawai T
      • Saito H
      • Marubayashi S
      • Yorioka N
      A case report of plasmapheresis in paraneoplastic cerebellar ataxia associated with anti-Tr antibody.
      • Esposito M
      • Penza P
      • Orefice G
      • et al.
      Successful treatment of paraneoplastic cerebellar degeneration with Rituximab [letter].
      Our case was unfortunate in that it was preventable. Undescended testis affects 2% to 5% of male neonates at term and is one of the most common congenital abnormalities. Among men who have had undescended testes, the risk of cancer is increased 2 to 8 times, and 5% to 10% of all men with testicular cancer have a history of cryptorchidism. Our patient would have been offered orchiopexy, standard treatment of persistent cryptorchidism, if he had presented when younger. Treatment of an undescended testis before puberty decreases the risk of testicular cancer.
      • Pettersson A
      • Richiardi L
      • Nordenskjold A
      • Kaijser M
      • Akre O
      Age at surgery for undescended testis and risk of testicular cancer.
      In young men, the possibility of testicular cancer makes anti-Ma antibodies especially important. These were tested for and were negative in our patient. Even when testicular tumor is not found, the presence of all of the following criteria should make the physician consider orchiectomy: (1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with anti-Ma2-associated encephalitis; (2) life-threatening or progressive neurologic deficits; (3) age younger than 50 years; (4) absence of other tumors; and (5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications.
      • Mathew RM
      • Vandenberghe R
      • Garcia-Merino A
      • et al.
      Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.
      Awareness is needed to increase early detection of paraneoplastic syndromes. The presence of specific auto-antibodies can be a useful diagnostic marker because the antibodies can direct the diagnostic approach. In addition, one should consider the common malignancies in the age group and perform the appropriate screening.

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      • CORRECTIONS
        Mayo Clinic ProceedingsVol. 83Issue 10
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          Misspelled last name: In the Residents' Clinic by Tafur et al entitled “28-Year-Old Man With Severe Vertigo,” published in the September issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2008;83(9):1070-1073), the second author's name was spelled incorrectly. It should be Lisa M. Baumann Kreuziger.
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