Lara Katzin

Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy.

Pompe disease, or glycogen storage disease type II, is a rare autosomal recessive disorder caused by mutations in the gene that encodes for α-glucosidase. Presentation in infancy is associated with respiratory failure, cardiomyopathy, and severe muscle weakness. Juvenile- or adult-onset cases typically present with proximal muscle weakness and are associated with respiratory insufficiency or exertional dyspnea. Treatment, until recently, was focused on supportive measures, and infants diagnosed with Pompe disease usually died within the first year of life. The recent development of recombinant α-glucosidase has dramatically improved the life expectancy and quality of life of infantile-onset disease with improvements in respiratory and motor function observed in juvenile- or adult-onset cases. This review focuses on the presentation, pathogenesis, diagnosis, and treatment recommendations for Pompe disease in this new era of enzyme replacement therapy.

Medical marijuana in neurology

Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are Δ9-tetrahydrocannabinol, which possesses psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy, migraine and weight loss. Data are also limited in regards to adverse events and safety. Common nonspecific adverse events are similar to those of other CNS ‘depressants’ and include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even with recreational use. There is a concern about psychological dependence, but physical dependence is less well documented. Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will likely expand.

Dural puncture headache, postpartum angiopathy, pre‐eclampsia and cortical vein thrombosis after an uncomplicated pregnancy

A 37-year-old gravida 2, para 2 woman developed a severe bi-frontal non-throbbing postural headache a few minutes after receiving epidural anaesthesia for labour. Her pregnancy was uncomplicated. There was no prior history of migraine, clotting disorders, or exposure to vasoactive drugs. The headaches persisted and she was treated with an epidural blood-patch on day 1 post-delivery for a presumptive diagnosis of low-pressure headache. The character of her headache changed from dull aching to constant throbbing. It now involved her entire head, was accompanied by nausea and vomiting, and did not have obvious precipitating or relieving factors. A non-contrast CT scan on day 4, performed at an outside hospital, was reportedly normal. Over the next 2 days she developed horizontal diplopia and right leg weakness. On day 6, a repeat non-contrast head CT scan showed a new small left posterior frontal hyperdensity, and she was transferred to our hospital. On admission she was afebrile, her blood pressure was 141/63 mmHg (different from her baseline of 120 mmHg systolic), and she had mild nonpitting leg oedema. Her neurological exam showed a right partial sixth nerve paresis, proprioceptive loss in the right lower extremity, and a wide-based gait with inability to tandem walk. Complete blood count and erythrocyte sedimentation rate were normal. Serum chemistries were notable for potassium 2.6 mmol/l, magnesium 1.4 mEq/l, and albumin 2.8 g/dL. Urine proteins were elevated at 2290 mg/l (normal, 0–135 mg/l). Repeat head CT with CT-angiography and CT-venography findings were consistent with a left posterior parietal infarction with an adjacent cortical vein thrombosis affecting the vein of Trolard (reported as a left frontal hyperdensity on the prior CT scan). In addition there was segmental narrowing and dilatation (‘beading’) of the bilateral middle, anterior and posterior cerebral arteries and their branches (Figure 1). Brain MRI showed similar findings: diffusion-weighted images showed a subacute infarct involving the left post-central gyrus; susceptibility images showed cortical vein thrombosis, and MRA showed beading in the proximal circle of Willis arteries (Figure 1). On fluid-attenuated inversion recovery (FLAIR) images, cortical vessels appeared hyper-intense, suggesting slow flow within segments of abnormally dilated vessels overlying the cortical surface as previously described in patients with cerebral vasoconstriction syndromes (1). Hypercoagulation panel tests (protein C, protein S, and antithrombin III levels, activated protein C resistance test, homocysteine, plasminogen, prothrombin gene mutation 20210 A, alpha 2 antiplasmin, tissue plasminogen activator inhibitor, and antiphospholipid antibody levels) were negative. Antinuclear antibodies were positive (1:320, speckled pattern); however, other tests for vasculitis were negative. On day 9, a repeat urinalysis showed no abnormality (urine protein level now 120 mg/l, Bence Jones proteins negative). The patient was treated with anticoagulation for cortical vein thrombosis (intravenous heparin transitioned to warfarin for 3 months). Her leg weakness resolved, the headache resolved gradually, and she was discharged on postpartum day 10. One week later, a repeat CT-angiogram and CT-venogram showed resolution of the cortical vein thrombosis and the postpartum angiopathy. When seen in follow-up (day 40 after delivery), her sixthnerve paresis and right leg proprioceptive deficits had resolved completely. doi:10.1111/j.1468-2982.2007.01285.x

Cerebral Infarction in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked form of muscular dystrophy characterized by progressive limb-girdle distribution of muscle weakness. Morbidity related to cardiomyopathy (CMO) is common, but cerebral infarction (CI) is relatively rare in these patients. We report a case of a pontine infarct in a patient with DMD and advanced CMO, and review the published data on CMO and CI in patients with DMD.

Review process for IVIg treatment: Lessons learned from INSIGHTS neuropathy study

Background This project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies. Methods A panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment. A second panelist reviewed the original record and follow-up records that were obtained for reauthorization of additional treatments and was asked to determine whether the patient had responded to the treatment. Results Our specialists believed that only 32.2% of 248 patients had an immune neuropathy and were appropriate candidates for IVIg therapy, whereas 46.4% had neuropathies that were not immune mediated. Only 15.3% of cases met electrodiagnostic criteria for a demyelinating neuropathy. Our specialists believed that 36.7% of 128 cases with follow-up records had responded to therapy. In cases in which the initial reviewer had predicted that there would be a response to IVIg, the second reviewer found that 54% had responded. This is compared with a 27% response rate when the first reviewer predicted that there would be no response (p = 0.019). Conclusions Our expert review finds that the diagnosis of immune neuropathies made by providers, and subsequently approved for IVIg therapy by payers, is incorrect in a large percentage of cases. If payers include an expert in their review process, it would improve patient selection, appropriate use, and continuation of treatment with this expensive therapeutic agent.

Multivitamin supplements and energy drinks in pyridoxine megavitaminosis

A 42-year-old woman with genetically confirmed but asymptomatic Huntington disease (HD) presented with a 2-year history of tingling along the lateral legs, intermittent band-like sensations in the legs that resolved with walking and worsened during rest, and searing pain from the knee down. She also noticed nocturnal leg jerking on days when she had energy drinks. She had no weakness, lower back pain, or bowel or bladder dysfunction. Family history was notable for HD in her brother and both parents. There was no significant alcohol use or other factors that may have contributed to her symptoms. Neurologic examination showed hyperreflexia in her legs but was otherwise normal (including intact perception of pinprick, light touch, and proprioception). She took duloxetine for anxiety and depression and zolpidem for insomnia. Diagnostic evaluation for multiple sclerosis, rheumatoid arthritis, and lupus was inconclusive. MRI showed mild C4–C7 posterior disk protrusions but no significant central or neural foraminal stenosis. Laboratory studies at presentation showed an elevated vitamin B6 (B6 or pyridoxine) level of 161.6 ng/mL (normal 2.1–21.7 ng/mL) and normal or negative complete blood count differential, metabolic profile (including fasting glucose), thyroid-stimulating hormone, vitamin B12, methylmalonic acid, antinuclear antibody, and Sjogren screen. Electrodiagnostic study showed no evidence of active lumbosacral radiculopathy or large fiber neuropathy. Additional history obtained following the discovery of elevated B6 levels revealed that the patient had consumed 2 energy drinks per day (40 mg of B6 each) for at least a year and one multivitamin tablet per day (100 mg of B6 each) for many years. One and a half months after stopping these sources of B6, the patient had dramatic improvement of her symptoms with only rare and transient recurrence.