Melissa Ortega

CLIPPERS COMPLICATING MULTIPLE SCLEROSIS CAUSING CONCERNS OF CNS LYMPHOMA

Melissa R. Ortega, MD Nida Usmani, MD Carlos Parra-Herran, MD David J. Adams, MD Brian Steingo, MD Kottil W. Rammohan, MD CLIPPERS COMPLICATING MULTIPLE SCLEROSIS CAUSING CONCERNS OF CNS LYMPHOMA Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disorder of the brainstem and cerebellum with distinct clinical and radiologic features.1 Coexistence of CLIPPERS and multiple sclerosis (MS) has never been previously described. We present a patient with MS who developed CLIPPERS shortly after natalizumab withdrawal, and the presentation raised concerns of primary CNS lymphoma which led to a brain biopsy. Awareness of this benign disorder may well have averted this biopsy. Recognition of CLIPPERS is crucial when one encounters perivascular enhancing lesions of the brainstem that are atypical for MS, but typical for this disorder.

Clinical Expression of Multiple Sclerosis in Hispanic Whites of Primarily Caribbean Ancestry

Objective: The clinical characteristics of multiple sclerosis (MS) are not well defined in Hispanic populations. We hypothesized that disease presentation in Hispanic white (HW) patients will be different from non-Hispanic white (NHW) patients given their ancestral background and reported lower disease prevalence. This study was undertaken to compare HW of primarily Caribbean ancestry to NHW on clinical characteristics of MS. Methods: We assessed 312 HW and 312 NHW patients with definite MS for clinical disease characteristics obtained through consented review of medical records. In order to assess the relationship between age-related phenotypes and ethnicity, linear regression was used. Logistic regression was used to assess the relationship between ethnicity and descriptors of disease presentation and severity as well as presence of neurological symptoms. Results: We observed a significantly younger age at diagnosis (p = 1.38E-02) and age at exam (p = 2.36E-05) in HW. However, age at first symptom did not differ significantly between the two groups. Furthermore, within HW, the mean age at first symptom and age at diagnosis was significantly younger in those born in the United States (p < 1.00E-03 for both). Interestingly, we noted an increase in ambulatory disability in HW patients, primarily among those with relapsing disease (p = 4.18E-03). Conclusions: We found several differences in age-related phenotypes and disease severity between HW of primarily Caribbean origin and NHW patients. To our knowledge, this is the largest study to date that examined the clinical characteristics of MS in Hispanic patients of largely Caribbean origin.

NMO spectrum presenting as partial myelitis

Sir, A 38-year-old right-handed African American woman presented in August 2011 to the emergency room with 2 weeks of progressive ascending numbness to below her abdomen. The patient reported no difficulty with ambulation, changes in urination or bowel movements, blurry vision or double vision. Her neurological exam revealed a thoracic (T10) sensory level to pinprick, decreased vibratory and proprioceptive sensation in both lower extremities, and hyperreflexia in the lower extremities. Magnetic resonance imaging (MRI) of the spinal cord showed a T2 hyperintense lesion associated with cord edema at T5–T6 that enhanced with gadolinium (Figure 1A). The remainder of the spinal cord was normal. Brain MRI revealed nonspecific bilateral subcortical frontal white matter T2 hyperintense lesions (Figure 1B). Serology including vitamin B12, methylmalonic acid, angiotensin converting enzyme, and serum protein electrophoresis were normal. Antinuclear antibody was weakly positive at 1:40. Antibodies to hepatitis A, B, and C, anti-Ro/ssa and ant-La/ssb, HTLV I/II, and Lyme disease were not detected. Cerebrospinal fluid (CSF) revealed 14 white blood cells, 1 red blood cell, normal protein and glucose, no oligoclonal bands, normal IgG index and cytology. CSF VDRL was negative. CSF polymerase chain reaction for Epstein–Barr virus, herpes simplex virus, cytomegalovirus, varicella zoster virus, and enterovirus were negative. The patient received intravenous methylprednisolone 1 g/day for 5 days with significant improvement in her neuropathic pain. She was placed on gabapentin for further symptomatic management. Serum and CSF NMO-IgG antibody tests were pending at the time of discharge. Six weeks later, the patient presented with severe allodynia from the breasts downward. Her exam revealed decreased strength in the right lower extremity, 4+/5 proximally and 2/5 distally. Laboratory tests were reviewed from her prior admission. CSF NMO-IgG antibody was negative, but serum NMO-IgG antibody was positive. MRI of her spinal cord revealed a longitudinally extensive T2 hyperintense lesion throughout her spinal cord from C2 to T7 (Figure 1C) with gadolinium enhancement from C5 to T7. The patient was again treated with intravenous methylprednisolone 1 g/day for 5 days with significant improvement in her weakness and allodynia. She was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) and initially placed on oral prednisone and azathioprine, but developed nausea, diarrhea, and elevated liver transaminases. She was subsequently treated with rituximab (two 1 g infusions at a 2-week interval) which she tolerated well. There are few reported cases in which NMOSD presents initially as acute partial transverse myelitis (APTM).1,2 A retrospective review of 22 cases of APTM by Scott et al.1 found only one case that was seropositive for the NMOIgG antibody. Although we do not advocate testing every patient with APTM for the NMO-IgG antibody, we do recommend close monitoring of these patients, as a minority will, in fact, develop NMO or NMOSD. This is clinically important as patients with NMO or NMOSD that are positive for the NMO-IgG antibody are at high risk for relapse3,4 and should be treated with immunosuppressants to prevent future attacks.

Fulminant myelitis with NMO IgG antibody following treatment with interferon alpha

A 62-year-old African American man with a history of positive hepatitis C antibody since 1991 was subsequently diagnosed with multiple sclerosis in 2000. The diagnosis of MS was based on several distinct episodes of vertical diplopia, gait imbalance, and left hemibody paresthesias. Cranial MRI showed periventricular white matter hyperintensities, including several ‘‘Dawson’s fingers’’ plaques. Cerebrospinal fluid contained oligoclonal bands. He was stable for 9 years on weekly injections of interferon b1a. Because of rising hepatitis C viral titers, all treatment was discontinued and treatment with interferon-a and ribavirin was instituted for 7 months until viral titers were undetectable. Two months after discontinuation of therapy, he developed acute quadriparesis and subsequent respiratory failure. On examination, both upper extremities were paretic and lower extremities were plegic and flaccid, with generalized areflexia. He had a thoracic sensory level at T3, and a positive Lhermitte’s sign. The MRI of the cervical spine revealed a contiguous hyperintense T2 signal extending from the cervico-medullary junction to the upper thoracic cord (Fig. 1), consistent with longitudinally extensive transverse myelitis. CSF analysis showed a markedly elevated protein level ([500 mg/dL) and no leukocytes. Serology tests for HIV-1, HTLV-1/2, anti-Hu, anti-Yo, anti-Ri, anti-nuclear antibody, SS-A, SS-B, angiotensin converting enzyme, and cryoglobulins were negative or normal. He was treated with intravenous methylprednisolone 1,000 mg daily for 5 days, followed by 27 g of intravenous immunoglobulin (IVIG) daily for 5 days. He received an additional steroid course with intravenous dexamethasone 4 mg every 6 h for another 9 days. He did not recover motor function after these treatments with corticosteroids and IVIG. One month after the acute onset of myelitis, he was transferred to a spinal cord rehabilitation center. With intensive physical therapy over 4 months, he regained some strength in his upper extremities, but his lower extremities remained plegic, and the T3 sensory level persisted. The NMO IgG antibody was detected by ELISA methodology in the serum approximately 2 months after the onset of myelitis symptoms. The test was repeated and the results were again positive. We document with this case the concomitant and unusual co-occurrence of NMO spectrum disorder in a patient with established multiple sclerosis. His prior demyelinating events never included optic neuritis or myelitis to suggest NMO or NMO spectrum disorder. Furthermore, a recent review of patients diagnosed as MS that subsequently tested positive for the NMO antibody found that they usually had certain clinical features including bilateral optic neuritis, recurrent optic neuritis with poor recovery, intractable hiccups/vomiting, periaqueductal lesions, or transverse myelitis that suggested NMO in hindsight [1]. This patient did not have any of those clinical or radiological features. Most importantly, this case illustrates the recognized propensity of patients with hepatitis C infection on N. Usmani M. McCarthy K. W. Rammohan M. R. Ortega (&) Department of Neurology, University of Miami, 1120 NW 14 Street, 13th Floor, Miami, FL 33136, USA e-mail: m.r.ortega@med.miami.edu

Focal segmental glomerulosclerosis secondary to subcutaneous interferon β-1a treatment in a patient with multiple sclerosis

Interferon (IFN)-β is a first line treatment for patients with relapsing remitting multiple sclerosis (RRMS) that has been shown to decrease relapse rates, reduce magnetic resonance imaging (MRI) disease burden and possibly delay onset of disability (Arnason, 2005). There are few reports of nephrotic syndrome related to Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS) during treatment with IFN-α (Nishimura et al., 2002; Tola et al., 2003; Rettmar et al., 1995). There are fewer reports of nephrotic syndrome induced by IFN-β (Tola et al., 2003; Auty and Saleh, 2005; Kumasaka et al., 2006). We report a 41 year old African American woman with RRMS that developed FSGS after 3 months of treatment with IFN-β-1a 3 times weekly and review the previously published cases.

Vitamin B12 deficiency mimicking NMO spectrum disorder

Sir, A 66-year-old right-handed woman presented with 2 months of paresthesias in both hands and subsequently developed numbness in the legs that ascended to her abdominal region. She was dropping objects due to the sensory loss, and she complained her gait was unsteady. She denied changes in urination or bowel movements. Her neurological exam showed normal mental status and memory. Strength was normal throughout except for the left upper extremity which was 4+/5. There was severe loss of proprioception and vibration in upper and lower extremities, more pronounced on the left. Deep tendon reflexes were 3+ throughout, and plantar response was flexor bilaterally. Romberg sign was present and she had difficulty with tandem gait. Magnetic resonance imaging (MRI) of the spinal cord showed a longitudinally extensive, nonenhancing T2 hyperintense signal extending from the cervicomedullary junction to T2 (Figure 1A and B) which raised concerns for a diagnosis of neuromyelitis optica (NMO). Cerebrospinal fluid (CSF) was normal without evidence for intrathecal IgG synthesis. Complete blood count was normal without anemia or macrocytosis. Serum vitamin B12 level was 128 pg/ml (>200), methylmalonic acid level was 5,560 nmol/l (87–318), and homocysteine level was 25.5 μmol/l (≤15). Parietal cell antibody was elevated at 86.5 units (≤20). Serum NMO-IgG antibody was negative. The patient received 3 months of biweekly 1000 μg cyanocobalamin injections and then continued on monthly 1000 μg cyanocobalamin injections in addition to receiving physical and occupational therapy. Repeat spinal cord MRI 4 weeks later showed T2 signal restricted to the posterior columns (Figure 1C and D). Vitamin B12 and methylmalonic acid levels had normalized. Four months later she complained of some residual paresthesias in her hands. Strength was normal. Proprioception and vibratory sensation were still diminished but improved, and gait had improved as well. Pregabilin was prescribed for symptomatic management. Vitamin B12 deficiency classically presents with macrocytic anemia and subacute combined degeneration of the spinal cord typified by distal paresthesias and spastic paraparesis. Although it has been reported to produce longitudinally extensive high signal on MRI, the signal is usually confined to the posterior columns.1–3 Our patient did not have anemia, but was markedly vitamin B12 deficient and had an elevated parietal cell antibody consistent with pernicious anemia. She presented with a myelopathy with striking high T2 signal seen throughout most of the spinal cord that appeared very much like longitudinally extensive transverse myelitis seen with NMO or NMO spectrum disorder. Although the abnormal cord signal improved significantly with replacement with cyanocobalamin, there was residual signal restricted to the posterior columns. This case highlights that all patients presenting with LETM should have vitamin B12, methylmalonic acid and homocysteine levels checked, especially if they are NMO-IgG seronegative as replacement with vitamin B12 may lead to significant neurological improvement.

Neurological complications of Hepatitis C infection

Though well-known as a cause of liver disease, Hepatitis C virus infection is emerging as a cause of a variety of peripheral and central nervous system disorders. The virus causes chronic persistent infection with complex immune responses in the majority of individuals. Viral infection may have the potential to generate neurological illness through direct infection of neural cells or through immune-mediated mechanisms, including enhancement of autoimmune responses. Moreover, the mainstay of antiviral treatment of hepatitis C infection, interferon-alpha, is itself associated with neurological morbidity. Thus neurologists are increasingly faced with diagnosing or even predicting a wide spectrum of neurological complications of hepatitis C infection and/or its treatment.

Native ancestry is associated with optic neuritis and age of onset in hispanics with multiple sclerosis

Hispanics with multiple sclerosis (MS) present younger and more often with optic neuritis (ON) as compared to Whites in the western United States. Regional differences related to Hispanic genetic admixture could be responsible. We investigated the association between global genetic ancestry and ON and age at onset of MS in Hispanics.

Contents Vol. 44, 2015

A. Anand, Chandigarh G.B.J. Anderson, Chicago, Ill. A. Barber, Auckland S. Barker-Collo, Auckland D.A. Bennett, Chicago, Ill. F. Bermejo, Madrid N.E. Bharucha, Mumbai G. Boysen, Copenhagen M. Brainin, Krems C. Brayne, Cambridge M.M.B. Breteler, Bonn A. Culebras, Syracuse, N.Y. R. D’Alessandro, Bologna J.F. Dartigues, Bordeaux J.L. Fisher, Columbus, Ohio G.M. Franklin, Seattle, Wash. M. Giroud, Dijon A.J. Hannan, Melbourne, Vic. G. Hankey, Perth, W.A. W.A. Hauser, New York, N.Y. M.A. Ikram, Rotterdam J. Kesselring, Valens C. Ketzoian, Montevideo S.J. Kittner, Baltimore, Md. Y. Kokubo, Osaka A. Korczyn, Tel-Aviv J.F. Kurtzke, Falls Church, Va. S.-M. Lai, Kansas City, Kans. L. Liu, Beijing M. Liu, Chengdu E.D. Louis, New Haven, Conn. S. Mehan, Sirsa M.M. Mehndiratta, New Delhi K. Nakashima, Yonago L. Nelson, Stanford, Calif. P.G. Parmar, Auckland P.-M. Preux, Limoges A.H. Rajput, Saskatoon, Sask. K. Rockwood, Halifax, N.S. P.M. Rothwell, Oxford R.L. Sacco, Miami, Fla. O. Shafey, Abu Dhabi Y. Shinohara, Tokyo W.F. Stewart, Danville, Pa. A. Thrift, Melbourne, Vic. T. Truelsen, Copenhagen C. Tzourio, Paris N. Venketasubramanian, Singapore H. von Holst, Stockholm W. Wang, Beijing International Association of Neurology and Epidemiology (IANE)