AN 88‐YEAR OLD WOMAN WITH LONG‐LASTING PARKINSONISM

CLINICAL HISTORY

An 88‐year‐old woman had been followed for several decades in our Movement Disorders Clinic for very long lasting Parkinsonism. In November 1918, while she was still nursing at age 3 months‐old, she and her mother were infected by epidemic encephalitis. Before the age of 10, dystonic postures of the lower limb occurred and progressively worsened, leading to orthopedic deformities. When she was 19, after her first pregnancy, a resting tremor appeared in the left hand. Akinesia and mild hypertonia occurred several years later, with partial improvement during the pregnancies. Her Parkinsonism worsened very slowly and after World War II she was confined to wheelchair. Her Parkinsonism improved with the introduction of levodopa, but severe adverse effects including choreic peak‐dose dyskinesia and dystonic movements occurred 3 years later. Mild psychiatric disorders appeared in the long term, along with obsessive compulsive disorders. In 1994, 70 years after the onset of extrapyramidal signs, global cognitive function assessed by the Mattis Dementia Rating Scale was normal for age: 138/144. Brain MRI was normal. ¹⁸Fluro‐Dopa PET demonstrated a severe bilateral and symmetrical reduction in fluoro‐dopa uptake which was more marked in the putamen than in the caudate. Fluctuant cognitive decline significantly occurred at the age of 87, with hallucinations. She finally died at the age of 88 years old.

GROSS AND MICROSCOPIC EXAMINATION

The brain and the spinal cord were obtained by autopsy. The right hemisphere and samples from brainstem and cerebellum were deep frozen for biochemical analysis. The left hemisphere, the spinal cord and most of the brainstem and the cerebellum were fixed in 10% buffered formalin. Gross examination showed mild atrophy of the temporal lobe (Figure 1) and the subthalamic nucleus, as well as loss of pigment in the substantia nigra (Figure 2). Microscopic examination showed moderate spongiosis and neuronal loss in the substantia nigra (Figure 3) and locus coeruleus, but no Lewy bodies were seen. Rare plaques were observed in the temporal and occipital cortex. Tau immunohistochemistry (using AD2, a monoclonal antibody raised against the phosphorylated serine residues 396–404 of tau) revealed sparse neurofibrillary tangles in the locus coeruleus (Figure 4) and the substantia nigra. The same lesions were more numerous and associated with threads in the subthalamic nucleus (Figure 5), the zona incerta, and hypothalamus. Neurofibrillary tangles, neuropil threads and some neuritic plaques were present in the entorhinal cortex, hippocampus and inferior temporal isocortex, but absent in frontal and parietal areas. Rare tau‐positive tufted astrocytes were also observed in the putamen (Figure 6), the pallidum, and the cerebellar white matter. Alpha‐synuclein immunostaining was negative. Brain homogenates containing 20 micrograms of total proteins from the temporal cortex (BA38), frontal cortex (BA10), primary motor area (BA4), parietal cortex (BA39), occipital cortex (BA18), hippocampus, pallidum, putamen, thalamus, subthalamic nucleus, mesencephalon and the medulla oblongata were loaded on SDS‐PAGE. Hyperphosphorylated Tau proteins were detected using AD2 antibody. We observed a pathological Tau triplet at 60, 64 and 69 kDa in the hippocampus, the temporal cortex, putamen, subthalamic nucleus, medulla oblongata and lightly in the pallidum, thalamus and mesencephalon (Figure 7). What is the Diagnosis?

Figure 1.

Figure 2.

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Figure 4.

Figure 5.

Figure 6.

Figure 7.

DIAGNOSIS

Post encephalitic Parkinsonism.

DISCUSSION

Survivors of the first wave of encephalitis lethargica (1917–1919) are now very rare all over the world. 40% of patients died during the acute phase of the disease. Extrapyramidal syndromes could occur in survivors just after acute phase or even several years later, in association with catatonia, obsessive‐compulsive troubles, or oculogyric crises. Despite the epidemic of lethargic encephalitis occurred simultaneously with the “Spanish” influenza pandemic, a link between the two disease was suspected, but disputed by Von Economo himself (5). Recent examination of archival tissue samples, using modern molecular biology techniques, failed to indentify the influenza virus in the brain of the victims (4). Post encephalitic Parkinsonism may be mediated by auto‐immune processes. In post encephalitic Parkinsonism patients, subcortical neurofibrillary tangles distribution is quite similar to progressive supranuclear palsy. They can also involve the hippocampus, the entorhinal cortex and also the temporal, frontal and insular cortices (3). But the biochemical profile of aggregated tau is the same of Alzheimer's disease: 3 bands at 60, 64 and 69 kDa (1). Tufted astrocytes were already observed, as well as astrocytic plaques (3). The full clinical, neuropsychological and neuro‐imaging data of our patient were already described (2). The relatively low amount of tau‐positive lesions could explain the long lasting and benign course of Parkinsonism in our patient.

ABSTRACT

We report the case of a woman who presented with a long lasting history of progressive Parkinsonism. She was affected by epidemic lethargic encephalitis in November 1918 at the age of 3 months. The infection was probably transmitted by her mother during lactation. Before the age of 10 years, she progressively developed dystonic postures of the lower limbs. When she was 19, a rest tremor appeared in the left hand. Later, akinesia and mild hypertonia occurred. Parkinsonism worsened very slowly but was improved with the introduction of levodopa (500 mg per day). She died at the age of 88. Brain autopsy was performed for neuropathological and biochemical analysis. Histologic findings were consistent with post encephalitic Parkinsonism, with tau‐positive neurofibrillary tangles, threads and tufted astrocytes in the pigmented nuclei of the brainstem, the cerebellum, basal ganglia and hypothalamus. Post encephalitic Parkinsonism is a rare encountered disease now, since survivors of the first wave of lethargic encephalitis (1917–1919) are very uncommon all over the world. But it is still often mentioned in the differential diagnosis of atypical Parkinsonism with tau pathology.