UCSF UC San Francisco Previously Published Works Title Neurologic Complications of Common Variable Immunodeficiency. Permalink https://escholarship.org/uc/item/9s0593dp Journal Journal of clinical immunology, 36(8) ISSN 0271-9142 Authors Nguyen, Jenna Thuc-Uyen Green, Ari Wilson, Michael R et al. Publication Date 2016-11-01 DOI 10.1007/s10875-016-0336-8 Peer reviewed eScholarship.org Powered by the California Digital Library University of California J Clin Immunol DOI 10.1007/s10875-016-0336-8 ORIGINAL ARTICLE Neurologic Complications of Common Variable Immunodeficiency Jenna Thuc-Uyen Nguyen1 & Ari Green 2,3 & Michael R. Wilson2 & Joseph L. DeRisi4,5 & Katherine Gundling1 Received: 20 July 2016 /Accepted: 15 September 2016 # Springer Science+Business Media New York 2016 Abstract Common variable immunodeficiency is a rare dis- Introduction order of immunity associated with a myriad of clinical mani- festations including recurrent infections, autoimmunity, and Common variable immunodeficiency (CVID) is a rare disor- malignancy. Though rare, neurologic complications have been der of immunity characterized by hypogammaglobulinemia, described in a small number of case reports and case series of impaired specific antibody responses, and variable T lympho- CVID patients. In this article, we present a patient with CVID cyte dysfunction. It can occur in both children and adults but is who suffered significant neurologic morbidity and categorize most commonly diagnosed in early adulthood. Although the reported range of neurologic complications associated CVID is commonly associated with recurrent infections, other with CVID. Our case highlights the complex nature of neuro- systemic conditions, such as autoimmunity, inflammatory dis- logic manifestations in CVID patients, and our review of the orders, and malignancy, have been well described [1]. current database suggests that infection and inflammatory Neurologic dysfunction in CVID is less frequently report- neurologic disorders are the cause of most neurologic ed, and the relationship to underlying immune dysfunction is presentations. not well understood. Current knowledge is based mostly upon case reports or small case series. In this article, we present a patient with CVID who suffered significant neurologic mor- Keywords Common variable immunodeficiency . bidity, we categorize the reported range of neurologic compli- Neurologic disease . Autoimmune cations associated with CVID, and we highlight some of the diagnostic and treatment challenges faced by clinicians who care for these complex patients. Electronic supplementary material The online version of this article (doi:10.1007/s10875-016-0336-8) contains supplementary material, Case which is available to authorized users. A 40-year-old woman with CVID developed neurologic and * Jenna Thuc-Uyen Nguyen ophthalmologic symptoms in 2009. Her complex history in- [email protected] cludes a diagnosis of CVID in 2007, with lymphocytic inter- stitial pneumonia (LIP), for which she was treated with my- 1 Division of Allergy and Immunology, University of California, San cophenolate mofetil (MM) with good benefit. Subsequently, Francisco, 400 Parnassus Ave, San Francisco, CA 94143, USA she developed lymphocytic colitis, and after attempting mul- 2 Department of Neurology, University of California, San tiple therapies without success, she was begun on Francisco, CA, USA adalimumab, which was associated with excellent improve- 3 Department of Ophthalmology, University of California, San ment of her diarrhea. MM was discontinued for a brief time Francisco, CA, USA during this treatment but restarted after decompensation of her 4 Department of Biochemistry and Biophysics, University of LIP, which again stabilized. California, San Francisco, CA, USA In August of 2009, she experienced subacute onset of blur- 5 Howard Hughes Medical Institute, Chevy Chase, MD, USA ry vision in her left eye that was associated with several weeks JClinImmunol of retro-orbital pain. She was given a 3-day course of methyl- There was a modest lymphocytic infiltration with predomi- prednisolone for presumed optic neuritis with improvement in nantly T cells (CD3+) and scant CD20+ cells. There were no her vision after 3 weeks from a visual acuity of 20/400 to 20/ granulomas identified and no tissue necrosis or viropathic 25. She was left with a mild residual left cecocentral scotoma changes seen (Table 2). Extensive infectious work-up, includ- that has been unchanged since that time with surveillance ing research-based metagenomic deep sequencing (MDS) of monitoring by her neuro-ophthalmologist. Several months lat- her CSF and brain tissue for the identification of potential er, she developed multifocal choroidopathy, which was pathogens revealed no specific etiology (Fig. 2). suspected to be inflammatory in origin. Subsequent retinal In October of 2014, the patient experienced a syncopal evaluations over the intervening years showed no progression. episode while running on a treadmill, which was followed In July of 2013, she presented with 6 weeks of episodic by postictal confusion. A repeat MRI demonstrated persis- visual distortion and headaches. On fundoscopic exam, she tence of the cerebellar lesions as well as new ill-defined areas had persistent multifocal choroidopathy, left optic disc pallor, of leptomeningeal enhancement, proximate to the right angu- and nerve atrophy consistent with her prior ophthalmologic lar gyrus, which was thought to serve as the seizure focus history. Cerebrospinal fluid (CSF) analysis demonstrated lym- (Fig. 2d). She was started on levetiracetam without any sei- phocytic pleocytosis with 34 WBCs, mildly elevated protein, zure recurrence. Repeat CSF analysis continued to demon- and greater than five oligoclonal bands. VDRL, VZV PCR, strate signs of inflammation (Table 1). and Lyme IgM/IgG were all negative (Table 1). MRI of her Given concern for infection in the setting of immunosup- brain, cervical, and thoracic spine were unrevealing. pression, or possible atypical demyelination, adalimumab was Peripapillary optical coherence tomography showed mild ret- discontinued. At this time, she continued to have left arm inal nerve fiber layer loss (87 μ OS versus 93 μ OD) with dysmetria along with new subtle imbalances brought out by modest but more significant loss of macular volume sugges- complex tasks (at baseline the patient was a high level endur- tive of some permanent ganglion cell loss. The precise etiolo- ance athlete). Neuropsychiatric testing demonstrated relative- gy of her inflammatory CSF and neurologic symptoms ly focal impairment in word retrieval. Understanding the small remained unclear. risk that her condition might be infectious in nature, she was In February of 2014, she developed new weakness of her given 3 days of methylprednisolone and experienced rapid left hand, along with tremor and poor coordination. She was improvement in balance, fine motor movement, short-term found to have left-sided dysmetria and an unchanged ophthal- memory, and word finding. MRI obtained shortly thereafter mologic exam. Brain MRI demonstrated two enhancing le- demonstrated interval decrease in the prominence of sions with mild mass effect in the left cerebellum (Fig. 1a). leptomeningeal enhancement about the bilateral superior cer- Repeat lumbar puncture (LP) showed similar CSF parameters ebellar hemispheres and right angular gyrus (Fig. 1e). A brain except for the presence of low numbers of neutrophils MRI obtained 2 months later, however, demonstrated an (Table 1). Histological analysis with two brain biopsies expansile lesion with increased T2 signal abnormality and showed modest astrogliosis (confirmed via glial fibrillary acid gadolinium enhancement involving the medial aspect of the protein immunohistochemistry) with superimposed nonspe- right posteroinferior cerebellar lobe (Fig. 1f). cific inflammation including otherwise normal architecture. Based upon her CSF results, lack of evidence for infection, Specifically, there was no evidence for myelin injury or loss. and good response to corticosteroids, rituximab was added to Table 1 Serial CSF analysis CSF studies 7/29/13 2/25/14 3/4/14 Reference ranges WBC 34 30 4 0–5/cc Poly 2 % % Lymph 74 % 78 % 86 % % RBC 5 4 none /cc Glucose 41 40 47 40–70 mg/dl Blood glucose 75 77 85 mg/dl Protein 66 51 42 15–50 IgG 3.7 2.9 3 0.3–4.3 Micro VZV PCR, VDRL, Lyme Ab negative VDRL NR IgG index 0.5 0.5 0.5 0.3–0.6 OCB >5 >5 >5 Cytology Mature lymphocytes and monocytes J Clin Immunol Fig. 1 Serial MRI brain images. a 2/2014 Two new enhancing lesions with mild mass effect in the left cerebellum on T1 post- gadolinium imaging (white arrows). b 4/2014 Near-complete resolution of left superior cerebellar hemispheric lesion. Unchanged left inferior cerebellar lesion (white arrow). c 5/2014 Increased conspicuity of leptomeningeal enhancement along the dorsal left paramedian cerebellum. Stable ill-defined enhancement (c1) and FLAIR hyperintensity associated with the inferior left cerebellar lesion (c2). d 10/2014 New ill-defined areas of enhancement principally confined to the leptomeninges and proximate right angular gyrus (arrow). e 11/2014 Interval decreased contrast enhancement about a left dorsal lateral cerebellar intraparenchymal lesion (not pictured), bilateral superior cerebellar hemisphere sulci (not pictured), and sulcus proximate to the right angular gyrus (arrow). f 1/2015 Edematous lesion with increased signal abnormality and enhancement involving the medial aspect of the right posterioinferior