Bettina Steiner-Birmanns

Phenotype in patients with Gaucher disease and Parkinson disease.

BACKGROUND Previous reports have shown an increased risk for Parkinson disease (PD) among type 1 Gaucher disease (GD) patients. However, the number of the reported cases of GD/PD is small and it is unknown whether certain GD phenotypes are associated with an increased PD risk. OBJECTIVE To present GD and PD characteristics of adults affected by both diseases from a large Israeli GD clinic, and assess whether certain GD characteristics are associated with a higher risk for PD. METHODS Medical files of patients >18years between 1990 and 2010 were reviewed for PD signs or symptoms. Available patients with PD underwent an additional neurological examination. Demographic and GD characteristics were compared between GD patients with and without PD using t-test and Fisher exact. Kaplan-Meier survival curves were used to estimate age-specific risk for PD among males and females. Age-specific risk for PD was compared between males and females using Cox Hazard ratio model. RESULTS 510 type 1 GD adults (233 males; 45.7%), were evaluated. 11 PD patients were identified (2.2%). Among those with GD/PD cognitive impairment was common (7/11). Two patients underwent successful deep brain stimulation (DBS). PD diagnosis was associated with male gender (81.8% versus 44.9% male, p=0.027) and older age (mean age, PD=62.8, non-PD=47.1, p=0.004). GD phenotype and severity did not differ between the two groups, including mean Zimran Severity Score index (7.7 versus 8.3), percent splenectomized (15.8% versus 27.3%), history of avascular necrosis (13.0% versus 27.3%) and percent ever treated with enzyme replacement (49.4% versus 45.5%). CONCLUSION Male gender and older age are risk factors for PD among GD patients, but GD severity is not associated with increased risk for PD. Further research is required to assess which GD patients are at a higher risk for PD, and why.

Strokes after cardiac surgery: mostly right hemispheric ischemic with mild residual damage

ObjectiveSince cardiac surgery is now performed on patients with high risk for cerebrovascular disease, we studied the clinical findings and medium term outcome of patients with acute stroke/transient ischemic attack (TIA) after cardiac surgery.MethodsAll consecutive patients with acute stroke/TIA after cardiac surgery were prospectively observed during a 19 month period. Follow-up was between 3 months and 21 months. Risk factors, type of stroke, anatomic localization, initial neurological deficit and followup outcome were evaluated, using standard assessment scores.ResultsAmong 406 patients operated (mean age 64.3 ± 12.7 years, 284 males), 18 developed stroke and 2 TIAs (mean age 65.7 years, 13 males). There were no cases of intracerebral hemorrhage. Most of the strokes happened shortly after valve surgery (mean 1.3 days post operatively) and were right hemispheric (right = 11, left = 3; p = 0.034).Vertebrobasilar stroke appearance was delayed (mean: 8.25 days post operatively); they were attributed mostly to cardiac arrhythmias. Stroke/TIA patients did not have a higher preoperative risk than those without, but their cardiac functional score was worse (p = 0.01), and the average cardiopulmonary bypass time during surgery was longer (p = 0.009). Two patients died in hospital, both with vertebrobasilar stroke.Most of the hemispheric stroke patients became functionally independent (mean modified Rankin Scale < 2), even those with initial severe deficit.ConclusionStrokes after cardiac surgery are mostly right hemispheric and exclusively ischemic. Outcome is relatively fair. We suggest an embolic injury to the right hemisphere, procedure related, as a possible mechanism.

Severe Methylenetetrahydrofolate Reductase Deficiency Clinical Clues to a Potentially Treatable Cause of Adult-Onset Hereditary Spastic Paraplegia

IMPORTANCE Hereditary spastic paraplegia is a highly heterogeneous group of neurogenetic disorders with pure and complicated clinical phenotypes. No treatment is available for these disorders. We identified 2 unrelated families, each with 2 siblings with severe methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting a complicated form of adult-onset hereditary spastic paraparesis partially responsive to betaine therapy. OBSERVATIONS Both pairs of siblings presented with a similar combination of progressive spastic paraparesis and polyneuropathy, variably associated with behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy, beginning between the ages of 29 and 50 years. By the time of diagnosis a decade later, 3 patients were ambulatory and 1 was bedridden. Investigations have revealed severe hyperhomocysteinemia and hypomethioninemia, reduced fibroblast MTHFR enzymatic activity (18%-52% of control participants), and 3 novel pathogenic MTHFR mutations, 2 as compound heterozygotes in one family and 1 as a homozygous mutation in the other family. Treatment with betaine produced a rapid decline of homocysteine by 50% to 70% in all 4 patients and, over 9 to 15 years, improved the conditions of the 3 ambulatory patients. CONCLUSIONS AND RELEVANCE Although severe MTHFR deficiency is a rare cause of complicated spastic paraparesis in adults, it should be considered in select patients because of the potential therapeutic benefit of betaine supplementation.

Spinal Cord Involvement in Uncomplicated Herpes Zoster

ABSTRACT We prospectively evaluated herpes zoster patients during the acute phase of the disease for central nervous system involvement. Of 24 patients with spinal zoster, 13 (54%) had spinal cord abnormality, which was asymptomatic in 12 of the 13. Age but not lack of acyclovir treatment was associated with such involvement. In all but 2, neurological involvement resolved within 6 months. Although the mechanism responsible for the neurological abnormalities is unknown, findings may support the hypothesis that zoster is associated with spread of viral infection into the spinal cord and therefore support the possibility that zoster is due to active viral replication in the ganglion.

Increased severity over generations of Charcot-Marie-Tooth disease type 1A

BackgroundCharcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance.ObjectivesWe set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations.MethodsThirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS).ResultsIn 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001).Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test).ConclusionsOur findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.

NONCONVULSIVE STATUS EPILEPTICUS IN OLDER PEOPLE: A DIAGNOSTIC CHALLENGE AND A TREATABLE CONDITION

To the Editor: Lacking the typical phenotypic features of seizures and the adverse systemic consequences of prolonged convulsions, nonconvulsive status epilepticus (NCSE) was incorrectly assumed not to cause neuronal injury. Unfortunately, NCSE is associated with morbidity and mortality due to neuronal damage from abnormal electrical activity and its association with the acute neurological disorders that may precipitate it. This becomes more apparent in the geriatric population, in which impaired baseline mental status hampers diagnosis even further, and the brain parenchyma is more sensitive to prolonged abnormal electrical activity. To determine the prevalence, clinical features, and course of NCSE in the elderly population, an observational prospective study was conducted of all consecutive patients with acute unexplained change in mental,cognitive, or behavioral status or confusion that was the cause of hospitalization or had occurred during hospitalization in the Department of Geriatrics, Shaare Zedek Medical Center, over a 24-month period. Typical electroencephalogram (EEG) changes were required to establish the diagnosis of NCSE. Clinical improvement was defined as resumption of the previous (baseline) mental status and disappearance of epileptic activity on EEG. Within a 2-year period seven of 307 hospitalized patients, aged 73 and older, were diagnosed with NCSE (Table 1). Of the seven patients (4 women and 3 men, aged 73–90, mean age 82.7), only one had a previous history of epilepsy; three had renal insufficiency. All patients presented with acute altered mental state: confusion, stupor or coma, without concomitant clinical convulsive activity. In three patients, the presenting symptom was refusal to eat. Time until diagnosis ranged from 1 to 5 days (mean 3 days). All seven patients had generalized NCSE on EEG that disappeared with intravenous diazepam injection (5–8 mg) in the five patients to whom it was given and in all patients on follow-up. None of the patients had focal status epilepticus on EEG. Patients were treated with an intravenous loading dose of phenytoin (800–1,000 mg) or valproic acid (20 mg/kg) followed by a maintenance dose. In six patients, clinical improvement was achieved within 1 to 4 days (mean 2.2 days). None of the medications that the patients were taking are known to cause seizures. In the patients with renal failure, the clinical and encephalographic improvement was chronologically related to the antiepileptic treatment and not to renal function improvement. One patient died of sepsis 19 days after the diagnosis of NCSE. All other six patients were discharged from the hospital after they regained their previous mental and neurological status.

Extended Phenotype in the Transthyretin Tyr77 Familial Amyloid Polyneuropathy

The transthyretin Tyr77 variant of familial amyloid polyneuropathy (FAP) has been identified in a few North American and European patients, but the full spectrum of its clinical manifestations is still not known. We report a 3-generation family of Jewish-Yemenite origin with Tyr77 FAP presenting with atypical features. The affected individuals had sensorimotor and autonomic neuropathy and cardiomyopathy accompanied by prominent dysphagia, hearing loss and asymptomatic carpal tunnel syndrome. Brain MRI in the proband showed multifocal white matter lesions. These features extend the reported Tyr77 phenotype and support the modifying effect of additional factors on the disease expression.

A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced β-glucocerebrosidase activity.

Action myoclonus renal failure (AMRF) syndrome is a rare form of progressive myoclonus epilepsy with renal dysfunction related to mutations in the SCARB2 gene. This gene is involved in lysosomal mannose-6-phosphate-independent trafficking of β-glucocerebrosidase (GC), an enzyme deficient in Gaucher disease. We report a family with myoclonic epilepsy, ataxia and skeletal muscle atrophy but without cognitive impairment or overt renal disease. A novel SCARB2 mutation was indicated by a striking discrepancy between lymphocyte and fibroblast GC activity in the proband evaluated for possible Gaucher disease. Our findings expand the genetic and phenotypic diversity of AMRF and suggest that low GC activity may present an important biochemical clue to the diagnosis of AMRF.

Prolonged propriospinal myoclonus following spinal anesthesia for cesarean section: case report and literature review.

Spinal myoclonus is a rare disorder characterized by sudden, shock-like, involuntary jerks that arise from the axial muscles and spread both rostrally and caudally through slow polysynaptic pathways [1, 2]. It has been reported as an adverse effect of anesthetic drugs, such as bupivacaine, morphine, propofol; psychiatric drugs, such as levodopa, imipramine; antiemetic drugs, such as metoclopramide, odansetron; antibiotics, and antihistamine drugs [3, 4]. With the patient’s agreement, we report case of prolonged spinal myoclonus following uneventful spinal anesthesia with sedation in an otherwise healthy woman undergoing elective cesarean section, our patient has had previously uneventful intrathecal and, later, general anesthesia, A 28-year-old healthy woman presented for term elective cesarean section (CS) because of two previous CS. A spinal block was performed at the Lumbar 3–4 level using a 27-gauge Whitacre pencil point spinal needle and 8 mg of 0.5% hyperbaric bupivacaine with 0.15 mg preservative-free morphine were administered slowly. A sensory block up to the thoracic 5 level (pin prick technique) associated with motor block was obtained prior to the start of surgery. During and after the procedure, the patient was stable hemodynamically and respiratory. Secondary to a restlessness of the patient and pain in the upper abdomen, she received ketamine 25 mg, midazolam 1 mg, and propofol 100 mg in the small intermittent doses, during the surgery which lasted 1 h. The operation proceeded uneventfully and a live female newborn (weight 3.606 kg; Apgar score 9/9 at 1st and 5th min) was delivered. Routine antibiotic prophylaxis (Cefazoline 1 g) was administered and 10 units of oxytocin in 1,000 mL of Ringer Lactate were started. In the recovery room, 1 h after the end of surgery and 2 h after the spinal block was performed, the patient developed involuntary, shock-like, rhythmic, symmetric contractions (jerks) of the lower limbs, lower abdominal wall, and to a lesser extent of the upper limbs’ muscular groups (see accompanying video). The patient was fully awake, hemodynamically and respiratory stable. The neurological and general examinations were otherwise unremarkable. A diagnosis of late pre-eclamptic toxemia was evoked and continuous intravenous administration of magnesium sulfate and propofol was started, but did not alter the symptoms. A neurological team consultation assumed that patient had myoclonus. An electroencephalogram (EEG) performed in the presence of active jerks showed normal brain activity. Work-up performed later, revealed normal routine blood and urine examinations, including normal serum calcium and magnesium level, and unremarkable findings of brain computerized tomography and magnetic resonance imaging of the brain and the whole spinal cord. Electrodiagnostic investigations showed normal nerve conduction studies and needle electromyography in the legs and arms. Administration of magnesium sulfate and propofol were stopped, because these drugs are not known to be effective in the management of myoclonic movement disorders. A. Lev Y. Gozal A. Ioscovich (&) Department of Anesthesiology, Perioperative Medicine and Pain Treatment, Shaare Zedek Medical Center, POB 3235, 91031 Jerusalem, Israel e-mail: aioscovich@gmail.com

The possible risk for strokes complicating cardiac surgery in patients with intraoperative hypothermia.

Background: The effect of hypothermia as a possible neuroprotective tool on the outcome of cardiac surgery is still controversial. Methods: We retrospectively assessed all patients who underwent cardiac surgery within a 14-year period and compared patients with and without postoperative stroke. Results: Stroke occurred more frequently in patients who underwent valve repair/replacement combined with coronary artery bypass grafting (CABG) than in patients who had CABG alone (p = 0.0002). All strokes (1.4%) were ischemic and mostly of large-vessel etiology. All patients with stroke had intraoperative minimal temperature <34°C. More patients in this group than in the group without stroke had an intraoperative minimal temperature <30°C (p = 0.01). Stepwise multivariate analysis of all pre- and intraoperative parameters identified significant risk factors for stroke: hypertension, diabetes mellitus and previous stroke as preoperative risk factors, but only lower minimal temperature as a significant intraoperative risk factor (p = 0.03; odds ratio 1.080/1°C, 95% confidence interval 1.004–1.152). The mean intraoperative temperature was 28 ± 4°C in patients who developed stroke and 30 ± 3°C in patients without stroke. Conclusions: Intraoperative hypothermia around 28°C might be harmful and associated with increased risk for postsurgical stroke.