Acta Neuropathol (1993) 86:405 - 410

HeuropathologKa �9 Springer-Verlag 1993

Striatonigral degeneration with neurofibrillary tangles K. Renkawek, M . W . I . M . Horstink

Institute of Neurology, University Hospital of Nijmegen, RO.Box 9101, NL-6500 HB Nijmegen, The Netherlands

Received: 22 March 1993/Revised, accepted: 17 May 1993

Abstract. An autopsy was performed on a 48-year-old woman with clinical features of parkinsonism-plus syn- drome with dominating akinesia. Neuropathological examination revealed striato-nigral degenerat ion (SND) and neurofibrillary tangles (NFT) characterizing pro- gressive supranuclear palsy. Such an unusual combina- tion of pathological findings may constitute a distinct clinico-pathological entity, with akinesia as the main clinical symptom, and with a pathological substrate of SND and NFT.We suggest that such cases ]nay establish a separate variant within multisystem atrophies syn- dromes.

Key words: Striatonigral degenerat ion - Neurofibrillary tangles - Akinesia

Striato-nigral degenerat ion (SND) is included as one of the multisystem atrophies (MSA) [23]. In addition to MSA, there are a number of other primary neuronal degenerations, such as progressive suprannclear palsy (PSP), all of which have a hypokinetic-rigid syndrome. The diagnosis of any individual parkinsonism-plus syn- drome may be complicated not only by an overlap in clinical features, but also in pathological findings [9, 10].

The pathological hallmarks of SND are degeneration of putamen and substantia nigra [1], and recently described cytoplasmic inclusions in oligodendroglia and in some neurons [16]. Lewy bodies and nenrofibrillary tangles (NFT) are not seen in this disorder. To our knowledge, SND or other variants of MSA have never been found together with PSR

The main neuropathological findings of PSR as described by Steel et al. [22] and confirmed by many others, are heterogeneous degenerat ion mainly in the basal ganglia, brain stem and cerebellum with a presence

Correspondence to: K. Renkawek

of NFT in damaged regions. Atypical cases of PSP are rarely described and they mainly concern a lack of ophthalmoplegia [4], and the presence of dementia or brain atrophy [2, 4, 13]. The coexistence of PSP with other neurological diseases is extremely rare [10, 20]. A rare subgroup of parkinsonian patients, who presented with akinesia as the predominant symptom, is proposed to be a subgrouping of PSP [14].

In the present study, we describe a patient with a parkinsonism-plus syndrome with dominating akinesia, whose overall clinical, magnetic resonance imaging (MRI) and neuropathological findings are compatible with SND and PSE

Case report

At the age of 38, a healthy woman noted slight stiffness and occasional mild tremor on the left side.When she was 41 years old she showed a generalized hypokinetic syndrome with slight rigidity (stage Hoen-Yahr III) and with remarkable dystonic hypomimia, moderate postural tremor, moderate dysarthria and dysphagia. Her posture was upright. She walked with normal velocity and stride but on a broad base. She fell frequently and suffered from freezing. Tendon reflexes were very brisk. Plantar reflexes were flexor. Madopar, 7 • 125 mg daily, had a moderate beneficial effect.

At the age of 43 the patient developed a disabling retrocollis, dyskinesia, grin-like facial dystonia, retraction of the upper eyelids, apraxia of eyelid opening, anarthria, severe dysphagia and dystonia of the feet. Supranuclear ophthalmoplegia, ataxia and orthostatic hypotension were absent. MRI revealed cerebellar and cortical atrophy. T2-weighted analysis showed dash-like increased signal intensities in both putamina. From the age of 47 the patient had to be hospitalized and tracheotomy was necessary for life- threatening inspiratory stridor.The patient died, aged 48, of central neurogenic respiratory disorder. As far as could be judged there had been no clear signs of dementia during life.

Material and methods

The brain was removed 24 h post mortem and fixed in 10 % buffered formalin for 1 month. The sections from the frontal, parietal, and temporal cortex, hippocampus, cerebellum, basal

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Table 1. Diagnostic cues for either striato-nigral degeneration (SND) or progressive supranuclear palsy (PSP) in this case

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Signs and symptoms [ref.] Observed in

SND a PSP a Patient Diagn. patient

Age of onset (years) 56 63 38 SND Duration (years) 5 6 10 = Akinetic-rigid + + + = Early rest tremor + + - = Early falls/gait + + + = Early ps. bulb. palsy + + + = Dystonic face [6] _+ + + PSP Apraxia eyelid [6] - + + PSP Retrocollis [6, 17] - + + PSP Pyramidal syndr. + + + = Downward gaze palsy ? [8] + - SND Orth. hypot. [7, 11] + - - = Dystonic feet + + + = Mental loss -+ + - = Resp. disturb. [12, 24] + - + SND L-Dopa effect + + + =

MRI: [5, 15, 19] Atrophy putamen midbr, putamen SND Decreased T2 (Fe) putamen ? [51 - = Cerebellar atrophy [21] + - + SND

Pathology: Max. cell loss and gliosis [4, 7, 22] putamen midbr, putamen/s, ni-

s.nigra s.nigra gra midbr. = NFT [4, 10, 22] - + + PSP Fe [1, 3] + - + SND Oligodendroglial inclusions [16] + - + SND

a References for SND [3, 7, 8, 11, 16, 18, 24]; for PSP [4, 6, 12, 22]; Diagn., Diagnosis, + , mostly present; +, infrequently pre- sent; - , mostly absent; = , not distinguishing; ?, uncertain, no downward gaze palsy explicitely mentioned; ps. bulb., pseudobul- bar; orth. hypot., orthostatic hypotension; rest. disturb., respiratory disturbance

ganglia and the brain stem were embedded in paraffin and stained with hematoxylin-eosin (H&E), Luxol fast blue (LFB), Masson- trichrome and PAS. Serial sections from the basal ganglia, thalamus, subthalamus, and the brain stem were additionally stained by Bodian, Bielschowsky, von Kossa (for calcium) and PeWs (for iron) methods. Gliosis was evaluated after glial fibrillary acidic protein (GFAP) immunoreaction performed with polyclonal antibodies (Dakopatt, Denmark) and avidin-biotin-peroxidase kit (ABC, Vector Labs). GFAP combined with Perl's method was performed on the sections from the basal ganglia and substantia nigra.

Neuropathological f'mdings

The brain weight was 1300 g Leptomeninges were thin, minimal atrophy of the frontal lobes and cerebellar hemispheres was

Fig. 1A-Fo A - D Marked degeneration of the putamen (A, luxol- fast blue), with fibrillar astrogliosis (B, GFAP), and iron accumu- lation (C, Perl's method). Degeneration of the substantia nigra (D, H&E). E ,F Cytoplasmic inclusions in oligodendroglia cells show- ing characteristic flame-shape (E, thin asterisk), degenerated neuronal fibers (thick asterisk) and intracytoplasmic inclusion in the neuron (F). Pontine basal nuclei. E ,F Bodian, A , D x 60; B,C x 200; E x 600; F x 350

present. On coronal sections both putamina were atrophic, and showed faint brown discoloration. Several minute lacunae were present in the putamen and globus pallidus. The substantia nigra was almost totally depigmented. Locus ceruleus was slightly discolored. The tegmentum was not atrophic. Inferior olives and dentate nucleus were well outlined.

Microscopic examination revealed rarefied structure of both putamina, marked loss of large and small neurons, fibrillar gliosis, and proliferation of capillaries (Fig. 1 A,B). Numerous granules, positive for iron were present freely in the tissue, within GFAP- positive hypertrophied astrocytes, and in occasionally remaining neurons (Fig. 1 C). Those granules were negative for calcium and they were not argentophilic.

The extension of the lesion was found in the external segment of the pallidum. Abundant polyglucosan bodies were present. The myelinated tracts transversing the putamen and globus pallidus were attenuated and pale. The caudate nucleus was not affected. The subthalamicus nuclei showed loss of neurons and gliosis. The thalamus was unchanged.

The substantia nigra showed severe loss of neurons in both the pars compacta and reticulata replaced by fibrous astrocytes. Numerous free granules of melanin pigment (H&E) and iron- positive granules were scattered in the neuropil (Fig. 1 D). Neither Lewy bodies nor NFT were found. The oculomotor nuclei showed loss of neurons.

In the locus ceruleus single neurons contained pale eosinophilic inclusions which were not argentophilic. The pontine nuclei were thinned. The cerebellar cortex was unremarkable. The dentate nucleus displayed mild loss of neurons. There were no pathological findings in the neocortex.

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Numerous intracytoplasmic inclusions were found in intrafasci- cular oligodendroglia (Fig. 1 E). They had a characteristic half moon-, or flame-like shape. The inclusions have been found in the putamen, pallidum, subthalamic nuclei, in striato-pallidal fibers, external capsule, pons, in the reticular formation of lower brain stem, and in the white matter of the cerebellum. In the basal pontis intracytoplasmatic inclusions were present in the neurons together with some samples of degenerated axons (Fig. 1 F).

NFT were found in the brain stem and subcortical gray matter. They were few in number in the putamen, and more numerous in the globus pallidus and subthalamic nuclei (Fig. 1 A). The nucleo- motor nuclei and the periaqueductal gray matter showed fibrillary degeneration of the most remaining neurons (Fig. 2 B-D). Single NFT were present in the locus ceruleus (Fig. 2 E). They were not encountered in the substantia nigra, but the cells which persisted were very few.

Numerously NFT were present in the basal pontine nuclei (Fig. 2 F,G). Both small and large neurons underwent fibrillary degeneration. They were located in bands of neurons of atrophic basal pontis nuclei together with oligodendroglial and neuronal inclusions. Most of NFT demonstrated globose type.

Discussion

The clinical signs and the character is t ic h is topathologi- cal a l terat ions found in our case co r re spond to those descr ibed in Table 1, summar iz ing the s y m p t o m s of bo th MSA, par t icular ly the SND type, and PSE Clinically the absence of oph tha lmop leg ia in a pat ient , who was o therwise very disabled,was the main reason to ques t ion the diagnosis PSP during life, a l though oph tha lmop leg ia except ional ly may never develop in an o therwise typical PSP [4].

O n neuropa tho log ica l study, this case revealed the typical features o f SND, such as p a t h o g n o m o n i c inclu- sions in o l igodendrogl ia [16] and above characteris t ic findings of PSR as far as the occur rence o f N F T was conce rned [22].

O u r pa t ien t is reminiscent o f Japanese cases of so-called pure akinesia [14, 25]. These pat ients showed degenera t ion o f pal l ido-nigral -subthalamicus regions, i ron deposits , and N F T b e y o n d d a m a g e d structures. Matsuo et al. [14] conc luded tha t pat ients with so-called "pure akinesia" ma y actually be a subgrouping of PSR O u r pat ient and the Japanese cases suggest the existence of a distinct c l inico-pathological ent i ty with akinesia as the main s y m p t o m accompan ied by clinical features reminiscent of M S A and PSR and with a pa thologica l ana tomica l substrate of M S A with NFT. T he diagnosis M S A is s t rongly suppor t ed by the widespread occur- rence o f character is t ic in t racytoplasmic inclusions in a high n u m b e r o f o l igodendrogl ia cells, and to a lesser degree in the neurons of basal pont is [16]. T h e y are no t

Fig. 2A-G. Neurofibrillary tangles (NFT) dispersed in subthal- amic nuclei (A) and periaqueductal gray matter (B). Characteristic globoid type of NFT (C). Degenerative changes in reticular formation of the brain stem with a presence of NFT (D, thin asterisk) and inclusions (thick asterisk). Degenerated neurons and NFT in the locus ceruleus (E). Numerous NFT in basal pontis (F,G). A-G, Bodian method. A,B,E • 120; C,G x 400; D • 350; F •

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descr ibed in PSR It suggests tha t our case seems to be a var iant within M S A syndromes .

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