Progressive Neurological Symptoms Research Articles

Surgical management of cervical deformity with osteotomy

Cervical sagittal balance is as an important clinical and radiographic parameter. The normal cervical spine is lordodic, and all kyphotic deformities should be explored. In patients with suspected cervical pathology, a thorough history and physical exam is mandatory. While axial neck pain commonly exists with kyphotic deformity, radiculopathy or myelopathy often exists as well. AP and lateral radiographs detect bony abnormalities and disc space collapse. A C2–7 plumb line may be drawn to measure angulation of the cervical spine. Adjuvant CT scan, to further delineate the bony architecture, and MRI scan, to assess for neural compression, are often useful in the management of a kyphotic spine. Nonoperative management is the usual initial mode of treatment. Physical therapy, aimed at posterior cervical paraspinal muscle strengthening, may improve lordosis in patients with flexible kyphosis. Anti-inflammatory medications and injections may cause symptomatic improvement but they do not address anatomic problems. Close follow-up is needed with these patients to monitor for neurologic deterioration. Operative treatment is indicated when nonoperative management has failed or in the setting of severe or rapidly progressive neurologic symptoms. Techniques for sagittal correction exist on a spectrum. Partial facet resections or Ponte osteotomies cause relatively small segmental lordosis but result in large sagittal improvement when used in long constructs. Anterior corpectomy with adjuvant posterior soft tissue release results in more focal lordosis. Three-column osteotomies are performed at either C7 or T1 to avoid the vertebral artery. Anterior column lengthening is relatively more powerful than a pedicle subtraction osteotomy. However, anterior lengthening is associated with a higher risk of damage to the surrounding neurovascular structures and soft tissue due to traction. Lastly, a vertebral column resection results in the greatest angular correction but is rarely performed due to its high potential for complication.

Canavan disease: clinical features and recent advances in research.

Canavan disease (CD) is a genetic neurodegenerative leukodystrophy that results in the spongy degeneration of white matter in the brain. CD is characterized by mutations in the gene encoding aspartoacylase (ASPA), the substrate enzyme that hydrolyzes N-acetylaspartic acid (NAA) to acetate and aspartate. Elevated NAA and subsequent deficiency in acetate associated with this disease cause progressive neurological symptoms, such as macrocephaly, visuocognitive dysfunction, and psychomotor delay. The prevalence of CD is higher among Ashkenazi Jewish people, and several types of mutations have been reported in the gene coding ASPA. Highly elevated NAA is more specific to CD than other leukodystrophies, and an examination of urinary NAA concentration is useful for diagnosing CD. Many researchers are now examining the mechanisms responsible for white matter degeneration or dysmyelination in CD using mouse models, and several persuasive hypotheses have been suggested for the pathophysiology of CD. One is that NAA serves as a water pump; consequently, a disorder in NAA catabolism leads to astrocytic edema. Another hypothesis is that the hydrolyzation of NAA in oligodendrocytes is essential for myelin synthesis through the supply of acetate. Although there is currently no curative therapy for CD, dietary supplements are candidates that may retard the progression of the symptoms associated with CD. Furthermore, gene therapies using viral vectors have been investigated using rat models. These therapies have been found to be tolerable with no severe long-term adverse effects, reduce the elevated NAA in the brain, and may be applied to humans in the future.

Outcome of early-treated type III Gaucher disease patients

Recombinant human acid β-glucosidase GBA (rhGBA) infusion is an effective therapy for non-neuropathic (type I) Gaucher disease (GD), but its effect on subacute neuropathic (type III) GD is still controversial. The most common genotype for type III GD is homozygous c.1448T>C (p.L444P) mutation, and in this study, we treated seven such patients starting from an early age (median 2.1 years; range 1-2.9 years). Before the start of treatment, all patients presented hepatosplenomegaly, anemia, and thrombocytopenia, but with no neurological signs. Normalization of hemoglobin levels and platelet numbers was achieved in all patients in one year. However, after a median treatment period of 7.6 years (2.2-12.0 years), two patients developed horizontal gaze palsy, one had seizures, four demonstrated mental retardation, and five showed kyphosis. Moreover, lymphadenopathy in the neck, thorax, or abdomen was observed in four patients. Therefore, the progression of neurological symptoms in these patients probably reflected the neurologic natural history of type III GD. Residual somatic symptoms, including kyphosis and lymphadenopathy, may be more common than what we thought. An additional treatment will be necessary to improve the outcome of type III GD.

Loss of LRPPRC causes ATP synthase deficiency

Defects of the oxidative phosphorylation system, in particular of cytochrome-c oxidase (COX, respiratory chain complex IV), are common causes of Leigh syndrome (LS), which is a rare neurodegenerative disorder with severe progressive neurological symptoms that usually present during infancy or early childhood. The COX-deficient form of LS is commonly caused by mutations in genes encoding COX assembly factors, e.g. SURF1, SCO1, SCO2 or COX10. However, other mutations affecting genes that encode proteins not directly involved in COX assembly can also cause LS. The leucine-rich pentatricopeptide repeat containing protein (LRPPRC) regulates mRNA stability, polyadenylation and coordinates mitochondrial translation. In humans, mutations in Lrpprc cause the French Canadian type of LS. Despite the finding that LRPPRC deficiency affects the stability of most mitochondrial mRNAs, its pathophysiological effect has mainly been attributed to COX deficiency. Surprisingly, we show here that the impaired mitochondrial respiration and reduced ATP production observed in Lrpprc conditional knockout mouse hearts is caused by an ATP synthase deficiency. Furthermore, the appearance of inactive subassembled ATP synthase complexes causes hyperpolarization and increases mitochondrial reactive oxygen species production. Our findings shed important new light on the bioenergetic consequences of the loss of LRPPRC in cardiac mitochondria.

Neurotropic T‐cell lymphocytosis: a cutaneous expression of CLIPPERS

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system that predominantly involves the pons and cerebellum and that improves with immunosuppressive treatment. Only recently described, the etiology is unknown, diagnosis is difficult and long-term neurological sequelae may occur without aggressive treatment. Herein, we describe a 59-year-old woman who presented with subcutaneous nodules affecting her face, trunk, limbs and an indurated annular erythematous lesion on her forearm. This was associated with marked dysesthesia of her skin, refractory to treatment. There was a 4-year history of dysequilibrium, vertigo, truncal and gait ataxia with progressive neurological symptoms. Skin biopsy of the annular nodular lesion showed a lymphohistiocytic infiltrate in dermis and subcutis with a striking lymphocyte-dominant infiltrate that was perineural and formed a nodular collection extending along a prominent subcutaneous nerve. Immunophenotyping indicated a marked predominance of T cells that were CD3 positive with a 2 : 1 CD4 : CD8 ratio. Scattered histiocytes were present but no well-formed granulomas or vasculitis. Magnetic resonance imaging studies showed changes in the pontine, brain stem and cerebellar region, which subsequently were defined as characteristic for CLIPPERS, but no brain biopsy was pursued. The marked neural skin symptoms and the cutaneous histopathological findings indicate that the skin may be an additional target organ in CLIPPERS, and the immune response may be directed against a common neural antigen. In radiologically typical CLIPPERS, identification of clinical skin lesions particularly subcutaneous nodules and biopsy may potentially form a basis for tissue diagnosis in this syndrome.

Unusual deterioration in a patient with multiple sclerosis on natalizumab therapy

Natalizumab is an effective treatment in patients with highly active relapsing-remitting multiple sclerosis (RRMS). However, its positive therapeutic effects have to be weighed against the potential serious adverse event of progressive multifocal leukoencephalopathy (PML). Thus, whenever patients with MS on natalizumab develop uncommon and progressive neurologic symptoms, the suspicion of PML has to be raised. The risk of PML becomes higher with increasing duration of natalizumab treatment, prior immunosuppressive treatment, and JC virus (JCV) antibody seropositivity.1 We here report a case of MS in which unusual symptoms in the context of 5 years of natalizumab treatment and seroconversion to JCV antibody positivity led to the initial suspicion of PML and a final diagnosis of Creutzfeldt-Jakob disease (CJD).

Neuromuscular complications after hematopoietic stem cell transplantation

The aim of this study was to analyze the occurrence of neuromuscular symptoms in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) for treatment of malignant hematopoietic disease. Among 247 outpatients after allogeneic HSCT, we conducted a prospective non-interventional study between July 2011 and August 2013. During follow-up visits, clinical and electrophysiological findings were correlated to the presence of autoantibodies/alloantibodies and to frequencies of lymphocyte subpopulations in peripheral blood. Resulting in an incidence of 8.1%, 20 patients were diagnosed with neuromuscular complications at a median onset of 12months post-transplant. Five patients (25%) were identified with polyneuropathy (PNP), ten patients (50%) with combined PNP and myopathy, four patients (20%) with myopathy or polymyositis (PM), and one patient (5%) with myasthenia gravis (MG). Immune-mediated sensorimotor PNP after HSCT is characterized by a predominantly axonal lesion and can be overlapping with neurotoxic side effects. The latency between HSCT and development of PM varied between 60days and 72months. In general, PM occurs parallel to graft-versus-host disease (GvHD) after tapering of immunosuppressive medication. Typical clinical features are proximal bilateral limb weakness with muscle atrophy. Autoantibodies (Ab) were detected in 12 patients, myositis-specific Ab only in one patient. In patients with progressive neurological symptoms, a decrease in the CD4/CD8 T cell ratio was observed. GvHD-related myositis appeared similar to idiopathic myositis regarding clinical and electromyographical findings. As outcome measure, sequential analysis of lymphocyte subpopulations in peripheral blood seems to be more suitable than Ab measurements. Whereas peripheral neuropathies are commonly observed shortly after HSCT, MG is a rare complication in the late post-HSCT phase.

An unusual case of Brown-Sequard syndrome

Idiopathic spinal cord herniation (ISCH) is a rare condition presenting as progressive Brown-Sequard syndrome in 66% of patients [1]. Other presentations include symmetrical spastic paraparesis (30%) or less commonly, pure sensory or motor deficits. The spinal cord protrudes through a ventral or ventrolateral dural defect, causing unilateral distortion to the lateral funiculus and giving rise to progressive neurological symptoms. The mean age at presentation is 53 years with a 2:1 female preponderance. First described by Wortzmann in 1974, there are now over 120 cases reported in the literature, however its pathogenesis remains unknown [1]. Postulated pathogenic mechanisms include both congenital dural abnormalities and acquired dural injury leading to cord herniation, exacerbated by cerebrospinal fluid pulsations during the cardiorespiratory cycle. The progressive nature of symptoms may be explained by the intra-operative observation of tethering of the cord at the margins of the dural defect [1–3]. The anatomy of the thoracic spinal cord is thought to contribute to the predisposition of ISCH to the thoracic cord. The thoracic kyphosis and the natural ventral position of the cord in themid-thoracic levels, combined with repeated flexion and extension movementare believed to aggravatedural injury in the thoracic region [4]. Diagnosis of ISCH ismadebyMRI.Diagnostic features includeventral displacementor ‘‘kinking’’ of the spinal cordat the level of thedural defect, enlargement of the dorsal subarachnoid space, cord signal changes and atrophic changes with thinning of the cord. Phase contrast MRI can be helpful in differentiating from an arachnoid cyst [5]. Surgical management of this patient involved a T6–T7 laminectomy and durotomy (Fig. 1). The herniated cord was gently retracted and the hernial orifice obliterated using a dural patch. At discharge on post-operative day 4, weakness was markedly improved with nearly full power, and sensation and reflexes were normal. The patient returned 3 months post-operatively for follow-up MRI (Fig. 2).

De ziekte van Creutzfeldt-Jakob bij een 80-plusser

Creutzfeldt-Jakob disease is a rare neurodegenerative disease that can occur in four forms. The sporadic form, the familial form, the iatrogenic form and variant Creutzfeldt-Jakob disease. The sporadic form is seen in about 1 per million people per year and is associated with rapidly progressive cognitive decline, psychiatric and neurological symptoms. The diagnosis and counseling of patients is a major challenge because of the complex and heterogeneous presentation, especially if the presentation differs from the standard. In this article we describe a diagnostic struggle regarding an elderly patient.

Clinical, Laboratory, Diagnostic, and Histopathologic Features of Diethylene Glycol Poisoning—Panama, 2006

Diethylene glycol is a toxic industrial solvent responsible for more than 13 mass poisonings since 1937. Little is known about the clinical spectrum, progression, and neurotoxic potential of diethylene glycol-associated disease because of its high mortality and the absence of detailed information in published mass poisoning reports. This incident includes the largest proportion of cases with neurotoxic signs and symptoms. We characterize the features of a diethylene glycol mass poisoning resulting from a contaminated cough syrup distributed in Panama during2006. This was a retrospective chart review and descriptive analysis in a tertiary level, urban health care facility. Acase was a person admitted to the Social Security Metropolitan Hospital in Panama City between June 1 and October 22, 2006, with unexplained acute kidney injury and a serum creatinine level of greater than or equal to 2 mg/dL, or unexplained chronic renal failure exacerbation (>2-fold increase in baseline serum creatinine level) and history of implicated cough syrup exposure. Main outcomes and measures were demographic, clinical, laboratory, diagnostic, histopathologic, and mortality data with descriptive statistics. Forty-six patients met inclusion criteria. Twenty-four (52%) were female patients; median age was 67 years (range 25 to 91 years). Patients were admitted with acute kidney injury or a chronic renal failure exacerbation (median serum creatinine level 10.0 mg/dL) a median of 5 days after symptom onset. Forty patients (87%; 95% confidence interval [CI] 74% to 95%) had neurologic signs, including limb (n=31; 77%; 95% CI 62% to 89%) or facial motor weakness (n=27; 68%; 95% CI 51% to 81%). Electrodiagnostics in 21 patients with objective weakness demonstrated a severe sensorimotor peripheral neuropathy (n=19; 90%; 95% CI 70% to 99%). In 14 patients without initial neurologic findings, elevated cerebrospinal fluid protein concentrations without pleocytosis were observed: almost all developed overt neurologic illness (n=13; 93%; 95% CI 66% to 100%). Despite use of intensive care and hemodialysis therapies, 27 (59%) died a median of 19 days (range 2 to 50 days) after presentation. A high proportion of patients with diethylene glycol poisoning developed progressive neurologic signs and symptoms in addition to acute kidney injury. Facial or limb weakness with unexplained acute kidney injury should prompt clinicians to consider diethylene glycol poisoning. Elevated cerebrospinal fluid protein concentrations without pleocytosis among diethylene glycol-exposed persons with acute kidney injury may be a predictor for progressive neurologic illness.

Loss of LRPPRC causes ATP synthase deficiency

Defects of the oxidative phosphorylation system, in particular of cytochrome-c oxidase (COX, respiratory chain complex IV), are common causes of Leigh syndrome (LS), which is a rare neurodegenerative disorder with severe progressive neurological symptoms that usually present during infancy or early childhood. The COX-deficient form of LS is commonly caused by mutations in genes encoding COX assembly factors, e.g. SURF1, SCO1, SCO2 or COX10. However, other mutations affecting genes that encode proteins not directly involved in COX assembly can also cause LS. The leucine-rich pentatricopeptide repeat containing protein (LRPPRC) regulates mRNA stability, polyadenylation and coordinates mitochondrial translation. In humans, mutations in Lrpprc cause the French Canadian type of LS. Despite the finding that LRPPRC deficiency affects the stability of most mitochondrial mRNAs, its pathophysiological effect has mainly been attributed to COX deficiency. Surprisingly, we show here that the impaired mitochondrial respiration and reduced ATP production observed in Lrpprc conditional knockout mouse hearts is caused by an ATP synthase deficiency. Furthermore, the appearance of inactive subassembled ATP synthase complexes causes hyperpolarization and increases mitochondrial reactive oxygen species production. Our findings shed important new light on the bioenergetic consequences of the loss of LRPPRC in cardiac mitochondria.

Avanços no Tratamento Endovascular dos Aneurismas da Artéria Carótida Interna Cavernosa

The cavernous aneurysms represent 3-11% of all intracranial aneurysms and about 14% of the internal carotid artery aneurysms. They represent a low risk of progressing to spontaneous subarachnoid hemorrhage, but can produce symptoms of compression to the cranial nerves, with the onset of retro-orbital pain or changes in the extrinsic ocular motility. The diagnostic investigation of these lesions consists of computed tomography, magnetic resonance imaging and cerebral angiography.The indication for treatment is questionable when symptoms are stable and well tolerated, especially in elderly patients. However, interventional treatment is indicated for patients with progressive neurological symptoms such as intense pain, and ruptured aneurysms. The ideal treatment is to exclude the aneurysm from the circulation, with preservation of the patency of the artery. However, the most widespread treatment is the occlusion of the internal carotid artery after undergoing carotid occlusion test. The purpose of this article is to critically review the literature regarding the carotid cavernous aneurysms, with special focus on therapeutic modalities available today.

Germinoma of the pineal region - a case report and literature review

Intracranial germ cell tumours (GCTs) are uncommon primary CNS tumours which resemble those originating in the ovaries or testes and predominantly arise in the first two decades. This report presents a case of a primary intracranial germinoma arising in the pineal region of a 28-year-old female. The patient presented with a 5 week history of headache and progressive neurological symptoms secondary to obstructive hydrocephalus. MRI demonstrated a large enhancing mass lesion in the region of the pineal gland with radiological features suggestive of a GCT (germinoma). Histologically, the tumour showed classical features of a pineal germinoma, with medium sized, round, uniform, poorly cohesive tumour cells amongst a fibrotic stroma with infiltrating lymphocytes. Immunohistochemical stains confirmed the histological diagnosis, with positive staining for C-Kit, OCT4 and PLAP. Negative staining was observed for CD30, synaptophysin, AFP, HCG and S100. Cerebrospinal fluid (CSF) cytology demonstrated no evidence of malignancy, with negative CSF and serum tumour markers (AFP and HCG). In summary, this case report presents a pineal germinoma arising in a young adult, use of immunohis-tochemistry for diagnosis and exclusion of differential diagnoses, with review and discussion of the literature.

Surgical treatment of idiopathic syringomyelia: Silastic wedge syringosubarachnoid shunting technique

Background:The underlying pathophysiology leading to syringomyelia is elusive with multiple flow-related theories constituting our current limited understanding of the disease process. Syringomyelia is associated with pathologies related to the disturbance of cerebral spinal fluid flow found in conditions such as Chiari I malformations, spinal malignancy, spinal cord tethering, trauma, or arachnoid adhesions. Our aim is to describe a unique surgical shunting technique used to treat refractory cases of idiopathic syringomyelia.Methods:Five patients, aged 22-50, presented with progressive neurologic symptoms associated with an idiopathic syrinx. All underwent decompressive laminectomy surgery with syringosubarachnoid shunting using the silastic wedge technique.Results:In five cases of idiopathic syringomyelia, clinical and radiographic follow up ranges from 3 to 36 months. Three patients have radiographic and clinical follow up greater than 24 months. All patients improved clinically and their symptoms have been stable.Conclusions:Shunting procedures for the syringomyelia disease spectrum have been criticized due to the inconsistent long-term outcomes. This surgical technique used to treat symptomatic idiopathic syringomyelia has been devised based on our intraoperative experience, surgical outcomes, and evaluation of the literature. The purpose of the wedges is to preserve patency of the communication between the syrinx cavity and the expanded subarachnoid space by preventing healing of the myelotomy edges and by maintaining an artificial conduit between the syrinx cavity and the subarachnoid space. Although short-term results are promising, continued long-term follow up is needed to determine the ultimate success of the silastic wedge shunting procedure.

A rare case of ataxia telangiectasia with intracranial tumor

Ataxia telangiectasia is a rare autosomal recessive multisystem disorder results in neurodegeneration, variable immunological abnormality that leads to recurrent sinopulmonary infection, febrile episodes, progressive cerebellar ataxia, ocular, and cutaneous telangiectasias. We report a case of 3-year-old Indian boy with recurrent episodes of fever and sinopulmonary infection and repeated hospitalization, rapidly progressive neurological symptoms. On clinical examination no ophthalmological or dermatological lesion was detected. On laboratory and immunological investigation polymorphonuclear leukocytosis with mild normocytic hypochromic anemia, IgA level of 39 mg/dl, alphafetoprotein level of 35 IU/L and normal interictal EEG was noted. Nerve conduction studies (NCS) was suggestive of wide spread early demyelinating polyradiculopathy. MRI shows a suprasellar tumor. The patient was diagnosed to be Ataxia telangiectasia (AT) according to diagnostic criteria of Ataxia-Telangiectasia Clinical Center. Patient was treated with pulse methyl prednisolone and IVIG. Further CD4/CD8 count, IgG subfraction estimation, leucocyte phagocytic activity and mutation analysis of ATM gene should be done to confirm the diagnosis.

Long-term follow-up on the effect of combined therapy of bile acids and statins in the treatment of cerebrotendinous xanthomatosis: A case report

Cerebrotendinous xanthomatosis (CTX; OMIM 213700) is a rare utosomal recessive inborn error caused by a deficit in bile acid synhesis. A deficiency of the enzyme sterol 27-hydroxylase causes the ccumulation of cholesterol and cholestanol in virtually all tissues. he molecular defect is localized to mutations of the CYP27A1 gene chrom. 2q33-qter), causing a variety of associated symptoms [1]. ystemic and neurological symptoms include intractable diarrhea, uvenile cataracts, tendon xanthomas, and progressive neurologic igns and symptoms. The systemic features typically appear at an arlier age than the neurological manifestations. The principal treatment for CTX is chenodeoxycholic acid CDCA), which inhibits excessive cholesterol and cholestanol ynthesis. Statins are currently thought to be beneficial, when comined with CDCA, yet this remains to be proven. Symptomatic herapies are also important.

Abstract P2-16-02: Bevacizumab, etoposide, and cisplatin (BEEP) is highly effective in brain metastases of HER2 positive breast cancer progressing from whole brain radiotherapy - Subgroup analysis of a multi-center phase II study

Abstract Background: We have recently reported that starting bevacizumab (BE) 1 day before chemotherapy could further induce tumor vascular normalization, thereby significantly enhanced the activity of etoposide (E) and cisplatin (P) in breast cancer patients (pts) with progressing brain metastases after whole brain radiotherapy (WBRT) (ESMO 2013). Lapatinib plus capecitabine is the only proven active regimen for the treatment of brain metastases of HER2 positive breast cancer, with a central nerve system (CNS) objective response rate (ORR) of 18-38% and median time to progression (TTP) of 3.6-5.1 months (mo) in those who had had prior WBRT. Material and methods: Twenty-three HER2 positive breast cancer pts with progressing brain metastases after WBRT were enrolled from Jan 2011 to Jan 2013. Protocol treatment was given in 21 day cycles: BE 15 mg/kg on day 1, E 70 mg/m2/day from day 2 to day 4, and P 70 mg/m2 on day 2 (BEEP regimen), for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS ORR. A CNS objective response was defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. This trial is registered with ClinicalTrials.gov (NCT01281696). Results: Median age was 55.1 (range 33-75); 9 pts were ER+, 14 pts were ER-; 15 pts were ECOG 0-2 (65.2%), and 8 pts were ECOG 3 (34.8%). All of them had previous exposure to trastuzumab, and 20 (87.0%) of them had received trastuzumab containing regimen for the treatment of metastatic disease. Eleven pts (47.8%) received lapatinib treatment before enrollment into this trial. The median lines of chemotherapy for the treatment of metastatic disease were 3 (range 1-8). The median BEEP treatment cycles were 6 (range 1-6). Sixteen of 23 pts (69.6%; 95%CI 47.1-86.8) achieved CNS objective response, including 6 pts (26.1%) with ≥80% and 10 pts (43.5%) with 50-80% CNS volumetric reduction, respectively. Five pts (21.7%) had 20-50% CNS volumetric reduction. Seven of 11 (63.6%) who were refractory to lapatinib treatment had CNS tumor response, and 9 of 12 (75.0%) who were lapatinib naive had CNS ORR. With median follow-up of 12.1 months (mo), the median time to progression was 7.7 mo (95% CI 6.6-8.8), and overall survival was 11.8 mo (95% CI 7.0-16.6) among the 23 pts. Only 3 pts (13.0%) had disease progression during protocol treatment. Grade 3/4 toxicities (≥1%) included neutropenia, leukopenia, thrombocytopenia, infection, anemia, and in 32.7%, 14.0%, 8.4%, 8.4%, and 5.6% per cycles, respectively. Ten pts (43.5%) needed dose reduction of E to 60 mg/m2 and P to 60 mg/m2, and 2 pts discontinued from treatment due to toxicity. Conclusions: BEEP regimen has a significant anti-tumor effect for HER2 positive breast cancer with brain metastasis which progresses after WBRT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-02.

Miglustat: A Review of Its Use in Niemann-Pick Disease Type C

Miglustat (Zavesca®, Brazaves®), a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis, is the only disease-specific drug approved for the treatment of progressive neurological manifestations of Niemann-Pick disease type C (NP-C) in adult and paediatric patients. NP-C is a rare, autosomal-recessive lipid storage disorder characterized by impaired intracellular lipid trafficking and progressive neurological symptoms leading to premature death. In a randomized clinical trial, long-term extension studies and a retrospective observational cohort study, treatment with oral miglustat stabilized key neurological manifestations of NP-C (including horizontal saccadic eye movement peak velocity, ambulation, manipulation, language and swallowing) in paediatric and adult patients with the disease. The therapeutic effects of miglustat in stabilizing or slowing disease progression have been confirmed in other reports in the clinical experience setting. The primary tolerability issues associated with miglustat are mild to moderate gastrointestinal effects (e.g. diarrhoea, flatulence and abdominal pain/discomfort) and weight loss, which usually occur during initial therapy and are generally manageable. In the absence of a cure, miglustat is a valuable agent to reduce the progression of clinically relevant neurological symptoms in paediatric and adult patients with NP-C, which is considered a significant achievement in the treatment of this disease.

Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: A clinical masquerader

Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature.

Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.