Address correspondence and reprint requests to Dr. J.P. O’Dwyer, Department of Neurology, St. Vincent’s University Hospital, Dublin 4, Ireland; e-mail: drjpodwyer@eircom.net Copyright © 2005 by AAN Enterprises, Inc. References 1. Gao FB. Understanding fragile X syndrome: insights from retarded flies. Neuron 2002;34:859–862. 2. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57:127–130. 3. Roth M, Tym E, Mountjoy CQ, et al. CAMDEX. A standardized instrument for the diagnosis of mental disorder in the elderly with special Systemic mastocytosis: A potential neurologic emergency G.B. Boncoraglio, MD; A. Brucato, MD; M.R. Carriero, MD; E. Maccagnano, MD; L. Robbiolo, MD; L.O. Scappatura, MD; D. Soligo, MD; and E.A. Parati, MD Mastocytosis refers to an uncommon and heterogeneous group of clonal hematologic disorders characterized by pathologic accumulation of mast cells (MCs) in various tissues. In 80 to 90% of cases, abnormal MC infiltration is restricted to the skin (cutaneous mastocytosis) and appears as small discrete red– brown maculae (urticaria pigmentosa); prognosis is favorable. By contrast, multifocal MC accumulation in extracutaneous organs (systemic mastocytosis [SM]) is potentially life threatening; the skin may or not be involved.1 The presenting signs and symptoms of SM are due to pathologic infiltration of MCs and release of their chemical mediators, primarily histamine. Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer. Sudden transient loss of consciousness and hypotensive or anaphylactic shock may also occur.2 Patients with undiagnosed SM can also present with neurologic symptoms.3 We describe a 64-year-old woman with unexplained recurrent episodes of loss of consciousness and neuroradiologic signs of chronic brain ischemia, who developed severe anoxic encephalopathy after hypotensive shock due to SM. Case report. The patient was admitted to our institute in September 2003. She reported a regular lifestyle, duodenal ulcer diagnosed at age 25, and allergy to acetylsalicylic acid. She had had a nonpruritic maculopapular rash on both legs and trunk since age 56 and recurrent episodes (about every 2 months) of flushing, palpitations, epigastric discomfort, and vomiting, sometimes followed by loss of consciousness for a few minutes with spontaneous recovery. For 2 to 3 days after these episodes, she experienced diffuse musculoskeletal pain and fatigue. In one episode, teeth grinding and incontinence occurred. In January 2003, she had had a sudden collapse followed by transient comatose state: hypotension and ST elevation were present on EKG, while echocardiography, coronarography, blood markers of cardiac ischemia, Holter EKG, and pulmonary scintigraphy were normal. Brain MRI revealed signs of chronic ischemic encephalopathy. In June 2003, she experienced acute transient loss of consciousness followed by confusion, loss of coordination, alexia, and agraphia. She was admitted to our institute for differential diagnosis between epilepsy and cerebrovascular disease due to heart condition or vasculitis. Physical and neurologic examinations were unremarkable except for multiple macular hyperpigmented lesions on the trunk and legs (figure). Blood tests were normal. On the second day, the patient developed sudden severe hypotensive shock followed by comatose state. Initially there was no palpable carotid pulse. A few days later, she recovered alertness but had global aphasia and spastic tetraparesis. Brain MRI showed acute anoxic encephalopathy (see figure). The skin biopsy finding (focal infiltrates of MCs) and the high serum tryptase level (156 ng/mL) were consistent with mastocytosis. After bone marrow biopsy and aspiration, SM with associated monolinear myelodysplasia was diagnosed. H1- and H2-Histamine receptor antagonists, sodium cromoglycate, baclofen, and risperidone were started. However, 5 months later, the patient had totally lost her independence, had fecal and urinary incontinence, and had received percutaneous 332 NEUROLOGY 65 July (2 of 2) 2005 reference to the early detection of dementia. Br J Psychiatry 1986;149: 698–709. 4. Shams’ili S, Grefkens J, De Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003;126:1409–1418. 5. Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460–469. 6. Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;74:1051–1056. 7. Willemsen R, Hoogeveen-Westerveld M, Reis S, et al. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet 2003;12:949–959. endoscopic gastrostomy; brain MRI showed remnants of the acute anoxic encephalopathy (see figure). Discussion. The clinical presentation of SM is extremely heterogeneous and may include loss of consciousness, seizures, cerebrovascular accident, headache, dizziness, or even transient chorea.3-5 Thus, undiagnosed SM may come to the attention of neurologists. The neurologic signs and symptoms seem more likely due to a direct effect of MC mediators or to hypotension than to MC infiltration of the CNS.4,5 However, death after rapid neurologic deterioration with postmortem demonstration of multiple cerebral infarcts with intravascular microthrombi and cerebral invasion by eosinophils (suggesting vasculitis) has been described.6 Recurrent syncope with fatal hypotensive shock has also been reported.7 Figure. (A and B) Urticaria pigmentosa appears as multiple macular hyperpigmented lesions, here on the left leg and right knee. (C through E) MRI in acute phase of anoxic encephalopathy: Axial proton density (PD) (C) and coronal fluid-attenuated inversion recovery (FLAIR) (D, E) images show high-intensity lesions involving basal ganglia (in particular putamen, globus pallidus, and caudate bilaterally) and frontoparietal cortex. (F through H) Five months later, axial PD (F), coronal FLAIR (G), and inversion recovery (H) images show that the hyperintense lesions of the basal ganglia are reduced, the frontal horns of the lateral ventricles are enlarged, and the frontoparietal cortex has atrophied (black arrow) with loss of normal signal intensity and enlargement of cerebral sulci (white arrow). The prevalence of SM according to the new diagnostic criteria1 is unknown, and SM is thought to be rare.1,2 However, because the clinical manifestations are so variable, the disease may often be undiagnosed, and patients presenting with neurologic manifestations may be more common than supposed. If not recognized promptly, SM can have the devastating outcome that characterized our patient. Furthermore, aspirin given to a patient with undiagnosed SM may precipitate fatal anaphylactic shock due to release of MC granule contents. Urticaria pigmentosa and unexplained recurrent episodes of flushing, palpitations, abdominal pain, and loss of consciousness with spontaneous recovery may alert the neurologist to a possible SM diagnosis. From Departments of Neurology (Drs. Boncoraglio, Carriero, and Parati) and Neuroradiology (Dr. Maccagnano), Istituto Nazionale Neurologico “Carlo Besta,” Department of Internal Medicine (Drs. Brucato and Robbiolo), Ospedale Niguarda Cà Granda, and Department of Hematology (Dr. Soligo), Ospedale Maggiore, Milano, and Department of Neurology (Dr. Scappatura), Pescopagano, ASL 1 Venosa (Pz), Italy. Received November 4, 2004. Accepted in final form April 6, 2005. Address correspondence and reprint requests to Dr. E.A. Parati, Department of Neurology, Istituto Nazionale Neurologico “Carlo Besta,” via Celoria 11, 20133 Milano, Italy; e-mail: parati@istituto-besta.it Neurologic oral manifestations caused by a new formulation of mirtazapine A. Kling, MD; R. Dahlqvist, MD, PhD; S. Johansson, PhD; M. Bäckström, PhLic; and T. Mjörndal, MD, PhD A conventional tablet of mirtazapine was introduced for treatment of depression in the mid-1990s. In February 2003, a new formulation of mirtazapine, the orally disintegrating tablet Remeron-S, was introduced in Sweden. The rationale is that patients experiencing difficulties in swallowing could let this new formulation melt before swallowing.1 In Sweden, health care professionals with permission to prescribe drugs, should report suspected adverse drug reactions (ADRs) to the regulatory authority, the Medical Product Agency, and the data are transferred online to the Swedish database (SWEDIS) for ADRs. The main aim of spontaneous reporting systems, such as the one in Sweden, is to produce signals regarding new potential ADRs. Methods. We examined all ADR reports in the SWEDIS database related to the conventional mirtazapine (Remeron), as well as those related to the orally disintegrating tablet (Remeron-S) that had been transferred to the database from January 1996 to September 2004. Furthermore, we compared these with other substances that had high total numbers of reports of paresthesia, and related to drug consumption measured as the number of defined daily doses (DDD). In brief, “DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.”2 Information about DDD was based on collected wholesale data from the national corporation of Swedish pharmacies. Results. We identified 368 ADR reports on mirtazapine, of which 329 were related to the conventional tablet formulation and 39 to the new orally disintegrating tablet. With 96 reports, neurologic symptoms were among the most commonly reported ADRs of mirtazapine. In addition, paresthesia was the most frequently reported ADR for mirtazapine on the whole. Furthermore, mirtazapine was one of the substances that most frequently had been reported for paresthesia. This became even more apparent when the ADR reports were related to drug consumption (figure). Thirty-three of the 41 reports about paresthesia concerned the conventional tablet of mirtazapine. In all these reports paresthesia was experienced in the extremities or generalized in the body. The remaining eight reports on paresthesia were related to the Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 26 issue to find the title link for this article Copyright © 2005 by AAN Enterprises, Inc. References 1. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603–625. 2. Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med 2004;55: 419–432. 3. Frijns CJ, Troost J. Generalized mastocytosis and neurological complications in a 71-year-old patient. Clin Neurol Neurosurg 1992;94:257–260. 4. Donnan GA, Jarrott BJ. Urticaria pigmentosa— change in conscious state associated with rise in plasma histamine levels. Clin Exp Neurol 1979;16:191–195. 5. Iriarte LM, Mateu J, Cruz G, Escudero J. Chorea: a new manifestation of mastocytosis. J Neurol Neurosurg Psychiatry 1988;51:1457–1458. 6. Jost E, Michaux L, Vanden Abeele M, et al. Complex karyotype and absence of mutation in the c-kit receptor in aggressive mastocytosis presenting with pelvic osteolysis, eosinophilia and brain damage. Ann Hematol 2001;80:302–307. 7. Roberts 2nd, LJ Sweetman BJ Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med 1980;303:1400–1404. new oral formulation of mirtazapine. In four of these eight reports the patients experienced oral paresthesia (see Cases 1 through 4 in table E-1 on the Neurology Web site at www.neurology.org). In addition, there were 10 reports (see Cases 5 through 14 in table E-1) of oral ADRs, related to the orally disintegrating tablet, describing symptoms from the mouth that we assessed as neurologic. In these reports the symptoms were described as anesthesia, numbness, sensory disturbances, or a sensation of swelling in the mouth after ingestion of the orally disintegrating tablet. The symptoms usually appeared shortly after intake and disappeared after a few hours. In all these cases the sensory symptoms were reversible. Discussion. From this survey, paresthesia seems to be a relatively common ADR associated with mirtazapine therapy. Spontaneous reporting of ADRs does not allow reliable calculations of incidence because of considerable underreporting. However, in our study, paresthesia was more frequently reported than ADRs like somnolence, dizziness, and weight gain, recorded in 0.4 to 5.9% in large clinical trials.3 The high number of oral neurologic manifestations associated with the use of the orally disintegrating tablet shows a new and fairly unique ADR. The mechanism responsible for the sensory ADRs of mirtazapine in general, and the oral sensory ADRs of the orally disintegrating tablet in particular, is unknown, but it is tempting to assume that the latter is mainly caused by a local action in the mouth. There are several possibilities as to why mirtazapine could induce paresthesia. One possibility is that mirtazapine causes paresthesia through a direct action on voltage-gated ion channels. A blocking effect on voltage-gated Ca2⫹ channels has, for example, been described in vitro for mianserin,4 an antidepressant substance closely related to mirtazapine. Since blocking of Ca2⫹ channels may lead to increased excitability via the effect of reduced intracellular Ca2⫹ concentration on Ca2⫹-dependent K⫹ channels, it is a plausible mechanism for the sensory symptoms caused by mirtazapine.5 Interestingly, from our survey, paresthesia is also a relatively commonly reported ADR for mianserin (see figure). An alternative mechanism is that paresthesia caused by mirtazapine is mediated via one or more types of monoaminergic receptors. Mirtazapine is an antagonist at adrenergic ␣2-receptors leading to an enhancement of noradrenergic and serotonergic neurotransmission. This results in increased stimulatory effects on serotonergic 5-HT1A receptors and adrenergic ␣1-receptors.3 Since paresthesia is also reported for other substances enhancing serotonin neurotransmission, e.g., sumatriptan,6 it is possible that 5-HT1 receptors are involved. The simultaneous blockade of other monoaminergic receptors may provide a further prerequisite for paresthesia. For example, antagonism of 5-HT2 receptors has been suggested to result in a greater binding of serotonin to 5-HT1A receptors.7 In conclusion, the discovery of the unexpected oral sensory July (2 of 2) 2005 NEUROLOGY 65 333 Systemic mastocytosis: A potential neurologic emergency G. B. Boncoraglio, A. Brucato, M. R. Carriero, et al. Neurology 2005;65;332-333 DOI 10.1212/01.wnl.0000168897.35545.61 This information is current as of July 25, 2005 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/65/2/332.full.html References This article cites 7 articles, 1 of which you can access for free at: http://www.neurology.org/content/65/2/332.full.html##ref-list-1 Citations This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/65/2/332.full.html##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Genetics http://www.neurology.org//cgi/collection/all_genetics Chemotherapy-tumor http://www.neurology.org//cgi/collection/chemotherapytumor Gait disorders/ataxia http://www.neurology.org//cgi/collection/gait_disorders_ataxia Tremor http://www.neurology.org//cgi/collection/tremor Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. 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