Abstract
Valproate and babies
Recently we cared for a baby with myelo-menigocoele from a mother prescribed sodium valproate for bipolar disease who had not been advised of the teratogenic effects of that drug or of the presumed usefulness of a larger dose of folic acid (5 mg instead of 0.5 mg) when pregnancy was possible. She had been taking 1500 mg per day for 5 years but stopped when she learned she was pregnant at 11 weeks gestation.
Valproate has been associated with a wide range of abnormalities in 17.1% of pregnancies [1]. To put this in perspective, the infamous thalidomide is believed to have caused a 20–30% rate of abnormalities. The abnormalities have affected the musculoskeletal system (62%), the cardiovascular system (26%), the genito-urinary tract (22%), the skin (30%), the respiratory tract (16%), and eyes and ears. Abnormalities in the neurological system include interruption of neural tube closure resulting in myelo-meningocoele (3%) and in neuronal migration and organization resulting in intellectual and behavioural difficulties, including autism spectrum disorder, in up to 29% [2].
The basic mechanism of teratogenicity is not known. Several are suggested: damage to genes programming early development and interference with cell differentiation and proliferation perhaps by an effect on the metabolism of folic acid. The therapeutic effect of valproate involves an increase in inhibitory neurotransmitters but that increase may interfere with neuronal migration and organization. The damaging effect of valproate is thus likely to exist throughout pregnancy.
In Australia it is not known how many women of child-bearing age are taking valproate but it is being prescribed in increasing amounts, especially for psychiatric disorders. Prescriptions have increased by 9% per year to a total of 188 463 in 2007 [3]. If each patient received four prescriptions a year and one-quarter were women of child-bearing age, this suggests that some 10 000 vulnerable women might be taking the drug.
It seems that prescribers of valproate for psychiatric disorder are not well aware of the teratogenic effects and this accords with a study in England in which documentation of advice about those effects was found in only 21% of cases [4].
Women of child-bearing age receiving valproate should be informed about contraception, the possible effects of the drug, the presumed usefulness of a higher dose of folic acid, and antenatal screening. Reduction of dose should be considered because Vajda et al. reported that embryopathy is unlikely if the mother is receiving <1000 mg per day, but the rate is still elevated, and increases with dose [5].
After birth the baby should be observed for signs of withdrawal from valproate, examined for the range of reported abnormalities, and followed for developmental abnormalities.
The teratogenic effect of valproate and similar drugs deserves further study. Pregnant women receiving anti-epileptic drugs for whatever reason may be encouraged to join the Australian Registry and participate in its voluntary questionnaires by telephone. It can be reached toll free on 1800 069 722.
Persisting visual phenomena following acute fear experiences: a possible visual state marker for post-traumatic stress disorder
We report a visual apperceptual phenomenon of ‘persistent peripheral oscillopsia’ (at 1–3 Hz) reported by certain patients when, with head and eyes held still, their steady gaze is maintained for more than a few moments on a stationary object. This visual anomaly, unobtrusive for most but for some significantly interfering with effective visual acuity, appears to have been initially but only briefly reported by an ophthalmologist in London in 1946 in association with ‘traumatic neurosis’ (sic) [6]. We find this to be reported by patients who report recurrent experiential iconic-type visual memory flashbacks, the iconic image being of what had been momentarily witnessed during the most frightening moment of a frightening experience in the past, possibly months or years in the past [7]. The reported causal experience and any persisting anxiety-related phenomena may or may not satisfy DSM-IV-TR criteria for post-traumatic stress disorder (PTSD) in terms of severity; when not, the clinical presentations appear as ‘subclinical PTSD’. Either way, the clinical presentations can be significantly disabling and may have medico-legal significance depending on the circumstances of the causal experience.
We also report that when the experiential iconic image is voluntarily evoked, and simultaneously subjected to repeated runs of rapid eye movement saccades, there is a high probability of a stepwise degradation and eventual elimination of the image and of any associated experiential phenomena of recall of the causal experience. Thereafter all subsequent recall of that experience remains in normal form [8]. If there are no other similarly abnormal experiential flashing-back memories from aspects of the same experience, or from other experiences, then oscillopsia is also reported to have been simultaneously degraded stepwise in range and amplitude, hand in hand with the degradation and depixilation of the iconic image. Thereafter peripheral vision remains oscillopsia-free, regardless of any persisting level of anxiety from other sources. We cannot report a neurological or other explanation for these consistent clinical observations.
This simply-tested-for oscillopsia appears to us to be a reliable visual state (? bio-) marker for this not uncommon form of subclinical/clinical PTSD. We find the subclinical form to be commonly reported by patients of any age above approximately 9 years with attention deficit hyperactivity disorder who present with comorbid disorder. Full clinical details of the observations over 25 years are reported on www.ptsdaustralia.com.
Intracranial gumma mimicking a cerebral tumour
Patients with syphilis rarely suffer from neurosyphilis and the incidence is estimated at 5–10% in untreated patients with syphilis [9]. We report a rare case of cerebral gumma in which magnetic resonance imaging (MRI) showed a focal mass lesion in the temporo-parietal region that disappeared following antibiotic treatment.
A 50-year-old woman without particular family or past history was admitted to National Hospital Organization Zentsuji Hospital for the evaluation of agitation and delusion. She noticed a small mass on the left side of her neck 2 years previously. On admission no neurological abnormalities were found except for miosises and sluggish light reflexes. On the left side of her neck there was a large mass, 10 cm in diameter, which was tender, immobile and extremely hard on palpation. Positive syphilis reactions were found in the serum (Rapid Plasma Reagin (RPR) test was positive with 1:3.9 titre; treponema pallidum hemagglutination assay (TPHA) was positive with 1:125; fluorescent treponemal antibody absorption (FTA-Abs) was positive). Both the TPHA and FTA-Abs of the cerebrospinal fluid (CSF) were also positive. Axial T1-weighted MRI of the brain showed a low-intensity lesion in the left temporo-parietal region, and axial T2-weighted and fluid attenuated inversion recovery (FLAIR) MRI showed a high-intensity lesion in the same area (Figure 1). Gadolinium-enhanced MRI showed linearly enhanced dura mater in the left parietal region. Histology of the cervical mass obtained at biopsy indicated carcinoma of the submandibular salivary gland. Whole-body 99mTc hydroxymethylene diphosphonate bone scintigraphy showed no evidence of bone metastasis, and cytology of the spinal fluid was negative for malignant cells. Considering these findings, metastatic brain tumour was ruled out and the diagnosis of neurosyphilis was then established. After treatment with 24 MU i.v. penicillin G daily for 3 weeks, cerebral MRI indicated complete disappearance of the abnormal lesion in the left temporo-parietal region, with no pathologic enhancement. CSF measurements were normal, with non-reactive RPR test. A serum assay for antibody to HIV was not conducted because consent was not obtained.
High-intensity lesion in the left temporo-parietal region on FLAIR magnetic resonance imaging.
A syphilitic granuloma, that is, gumma, often forms a mass lesion attached to the dura mater [10] and there is also a case of cerebral gumma showing dura enhancement on MRI. Dural enhancement may occur adjacent to the brain tumours, however, as a result of tumour cell invasion or connective tissue proliferation [11]. Therefore, the radiological findings of cerebral gumma may mimic those of other intracranial mass lesions, especially brain neoplasms, and definitive diagnosis has always been difficult [10], [12]. Godt et al. claimed that complete disappearance of the computed tomography (CT) findings after penicillin therapy could be considered proof of the syphilitic aetiology of the mass lesion [13]. This case suggests that cerebral gumma should be considered in the differential diagnosis in any patient found to have a cerebral mass lesion on CT and MRI.