Ocular outcome and frequency of neurological manifestations in patients with acute posterior multifocal placoid pigment epitheliopathy (APMPPE)

APMPPE is a rare disease, and therefore, there are not many systematic reports in the literature. So far, mainly case reports but also some studies with case series have been published. Most studies were done retrospectively as this is often the case with rare diseases. The published studies are difficult to compare and to summarize because emphasis was put on different aspects of the disease. In our study, we focused on two aspects of the disease: the visual, overall outcome and CNS involvement. Seventy-two percent of our patients were examined in a prospective follow-up exam.

Visual loss is the most obvious symptom for the patient and brings the patient to the ophthalmologist. Visual recovery is the most important aim for the patient and the ophthalmologist. In our group of patients, the mean finally measured visual acuity was 0.09 logMAR. Half of the patients had an improvement of visual acuity in the worse eye (mean final visual acuity, 0.17 logMAR) compared to the date of presentation (mean, 0.64 logMar). The other half remained stable (mean first and final visual acuity, 0.03 logMar) but had an overall better initial visual acuity. That visual recovery may be incomplete in some patients is in agreement with Fiore et al. [3]. They found in an extensive literature review as well as in a group of their own patients that APMPPE has a relatively benign visual prognosis, but compared to other white dot syndromes, there are patients with incomplete visual recovery. Fiore states, in agreement with other relatively recent reports [4, 5], that nearly 50 % of the eyes reached an incomplete recovery in visual acuity (≤0.1 logMAR) and that approximately 25 % of the eyes have a more limited visual recovery (≤0.3 logMAR). In contrast, some older publications describe a good visual prognosis [6-9]. A long-term study (average follow-up 5 years) conducted by Gass [10] revealed that only 2 out of 59 eyes achieved a visual acuity less than 0.18 logMAR. Our study also revealed a good outcome looking at visual acuities, but all patients showed scarring of the posterior pole that was mirrored by persistent visual field defects in the central 30° in two thirds of the patients examined. Still, good reading abilities were shown in those patients where near distance visual acuities were obtained, albeit with metamorphopsias in all of these patients. As APMPPE is a disease that afflicts relatively young patients, we need to find out how we can prevent the scarring and thus improve outcome.

Neurological involvement may not be as obvious as the reduction of visual acuity. We observed mainly headaches which occurred in half of the patients. Of patients with headaches, only four described flu-like symptoms. Headaches can represent a neurological symptom on its own or can be part of the flu-like symptoms which patients sometimes report. The most severe neurological complication we witnessed was stroke caused by histologically proven cerebral vasculitis. In a Medline search, we found 31 APMPPE patients with neurological manifestations [2, 3, 11–18]. Cerebral stroke occurred in 16 cases. Our case series adds another 11 patients with neurological symptoms and 1 with cerebral stroke. Several authors describe angiography findings that are in line with cerebral vasculitis (e.g. focal stenosis, lumen fluctuation), but in only two cases, vasculitis was histologically proven [19–21].

Other neurological manifestations that are described in the literature are vertigo, dysarthria, ataxia, tremor, paraesthesias, migraine and cavernous sinus thrombosis [14]. Of note in our study was the fact that MRI results did not necessarily correlate with CSF abnormalities. Patients 5 and 6 (Table 2) had normal MRIs but abnormal CSF findings. Vice versa, our stroke patient (patient 8) displayed pathological findings at cranial MRI, yet had a normal CSF. Pathological CSF results in APMPPE patients with or without major neurological complications have been described [22–24].

We did not detect a clear correlation between ophthalmologic impairment and the rather heterogeneous neurologic manifestations. For example, patient 8, the patient with the worst neurological complication, also had one of the worst visual acuities and MD values. In this case, there is a positive correlation. On the other hand, patient 5 who had headaches and changes in the CSF had a very good visual acuity (V/A) and visual field. Ophthalmologic findings in patient 6 illustrate that even visual acuity and visual field do not necessarily correlate. This patient who complained of different neurological symptoms and had changes in the CSF had a very good V/A, but pronounced field defects. Depending on the localisation of the retinal lesions, especially the involvement of the fovea, patients might have a good V/A, but a bad visual field. To judge if a patient is in danger of neurological complications, the severity of the visual loss and field defects are not a reliable marker. We think that it is more helpful to explicitly ask the patient about neurological symptoms and in the case of doubt lean towards lumbar puncture to rule out CNS involvement. Other non-invasive neurological examinations may be superior (manuscript in preparation).

We conclude that neurological signs and symptoms, especially headaches, are frequent in APMPPE and should be taken seriously. Adequate investigations including MRI and CSF examination should be initiated in these patients. Our patients with persisting neurological symptoms and suspect MRI or CSF results were monitored closely by us and the neurologists. It may be discussed that CSF investigations should be performed even in an asymptomatic, MRI negative APMPPE patient as ocular symptoms may precede neurologic symptoms or ophthalmic treatment may masquerade neurologic manifestation. If neurological symptoms persist despite treatment, it might even be advisory to repeat MRI or CSF as we learn from our stroke patient where the initial MRI and CSF were not able to identify vasculitis. Immunomodulatory treatment might be of prognostic relevance, but no prospective studies have been performed. It is unlikely that they will ever be performed, as the disease is so rare. In our cohort, only three patients did not receive treatment, and their outcome did not differ from the rest of the group. At the same time, 80 mg of prednisone did not prevent the stroke in the described patient. Some authors question the need to treat APMPPE patients arguing that therapy does not alter the natural course of the disease [10, 18, 25]. Fiore et al. [3] conclude that the use of oral corticosteroids remains unclear and that more definitive data are required. Several authors agree that rapid treatment is indicated when CNS complications accompany APMPPE [2, 22].

We think that the very high corticosteroid starting dosages (>1 mg/kg body weight) which were chosen in some of the patients by the physicians on duty for the ophthalmologic aspect alone were too high. But, if one considers the assumed pathogenesis, an immune hyperreactivity after a viral infection, it feels like a logical consequence to use oral corticosteroids to soften that immune response. At the same time, it may prolong ongoing viral activity.

In conclusion, we have shown in this case series of 18 patients that visual prognosis is good in patients with APMPPE, but visual field defects may remain, significantly reducing quality of vision in the majority of the patients. Neurological complications may be serious and have to be considered at the time of diagnosis of APMPPE. Concluding from our results, all patients with the diagnosis APMPPE should receive a clinical neurological examination, cerebral MRI and TCD with subsequent lumbar puncture if any of these three shows abnormalities. Treatment with oral corticosteroids should be discussed with the neurologists and with the patient as a benefit over natural history cannot be guaranteed.