Alaskan Husky encephalopathy - UC Davis School of Veterinary

Acta Neuropathol (2000) 100 : 50–62
© Springer-Verlag 2000
R E G U L A R PA P E R
Ori Brenner · Joseph J. Wakshlag ·
Brian A. Summers · Alexander de Lahunta
Alaskan Husky encephalopathy –
a canine neurodegenerative disorder resembling subacute
necrotizing encephalomyelopathy (Leigh syndrome)
Received: 6 August 1999 / Revised, accepted: 18 October 1999
Abstract The gross and histopathological findings in the
brain and spinal cord of five Alaskan Husky dogs with a
novel incapacitating and ultimately fatal familial and presumed hereditary neurodegenerative disorder are described. Four dogs presented with neurological deficits
before the age of 1 year (7–11 months) and one animal at
2.5 years old. Clinical signs in all dogs were of acute onset and included ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulties in prehension of food. In animals allowed to survive, the disease was static but with frequent recurrences. Pathological
findings were limited to the central nervous system.
Grossly visible bilateral and symmetrical cavitated foci
were consistently present in the thalamus with variable
extension into the caudal brain stem. Microscopic lesions
were more widespread and included foci of bilateral and
symmetrical degeneration in the basal nuclei, midbrain,
pons and medulla, as well as multifocal lesions at the base
of sulci in the cerebral cortex and in the gray matter of
cerebellar folia in the ventral vermis. Neuronal loss with
concomitant neuronal sparing, spongiosis, vascular hypertrophy and hyperplasia, gliosis, cavitation and transient
mixed inflammatory infiltration were the main histopathological findings. In addition, a population of reactive
gemistocytic astrocytes with prominent cytoplasmic vacuolation was noted in the thalamus. Lesions of this nature
in this distribution within the neuroaxis have not been reported in dogs. The neuropathological findings resemble
Leigh’s disease/subacute necrotizing encephalomyelopathy of man. Neuronal sparing in conjunction with apparently transient astrocytic vacuolation point to the pos-
O. Brenner · J. J. Wakshlag · B. A. Summers · A. de Lahunta (!)
Department of Biomedical Sciences,
College of Veterinary Medicine, Cornell University,
Ithaca, NY 14853-6401, USA
Fax: +1-607-253-3541
Present address:
O. Brenner
Experimental Animal Center,
The Weizmann Institute of Science, Rehovot 76100, Israel
sible pathogenetic role of astrocytes in the evolution of
these lesions. An inherited metabolic derangement of unknown nature is postulated as the cause of this breed-specific disorder.
Key words Dog · Alaskan Husky · Metabolic
encephalopathy · Leigh’s disease · Subacute necrotizing
encephalomyelopathy
Introduction
Since its initial description in 1951 [25], the term Leigh’s
disease (LD) or, more appropriately, Leigh syndrome (LS)
[12, 50] has been used in human neurology and neuropathology to designate patients with characteristic bilateral and symmetrical brain stem lesions that feature tissue
destruction, capillary proliferation, and neuronal sparing.
The precise distribution of lesions within the brain stem
and involvement of other parts of the central nervous system (CNS) vary [9, 16, 27]. Until the 1980s, variability in
the clinical presentation of LS allowed confident diagnosis to be established only by postmortem examination [46,
50]. In the last few years, clinical and neuroradiological
findings have been defined and permit antemortem presumptive diagnosis [12, 21, 43, 45, 49]. Investigations of
LS have revealed an array of biochemical and genetic abnormalities, clearly demonstrating that the characteristic
complex of neuropathological features traditionally required to make this diagnosis does not correlate to a single
and discrete disease entity. Rather, it has been proposed
that LS may be viewed as a paradigm in that it represents
the response of the developing CNS to energy deprivation
[12]. Currently, some 75% of the cases in which the typical phenotype of LS is found are known to be caused by
diverse defects of the mitochondrial respiratory chain.
The cause of the remaining cases is unknown [12].
In 1992, one of us (A.D.) recognized a novel degenerative disease affecting the CNS of juvenile Alaskan
Husky dogs. Between 1992 and 1998 neurological and
neuropathological studies were carried out at our institu-
51
Table 1 Signalment and clinical signs of five Alaskan
Husky dogs with Alaskan
Husky encephalopathy
a All
dogs were euthanized
Dog
Gender
No.
affected/
litter size
1
F
2/4
7
10
2
M
1/5
9
14
3
4
5
F
F
F
2/4b
2/4b
2/6c
8
11
30
10
18
32
b Littermates
c An
affected female littermate
was diagnosed by computed
tomography at the age of 2.5
years and died naturally at 4
years old
Age at
Age at
Clinical signs
onset
death
(months) (months)a
Ataxia, visual deficits, propulsive behavior
abnormal prehension
Ataxia, visual deficits, propulsive behavior
abnormal prehension
Ataxia
Seizures, episodic ataxia, visual deficits
Episodic seizures, semicoma, ataxia,
propulsive behavior
tion on five Alaskan Husky dogs (four females and one
male, from four litters) with this condition (Table 1).
Pathological findings of the first cases (dogs 1 and 2 of
this report) have been briefly reported [42]. Here we present the first comprehensive neuropathological description of this disorder based on necropsy studies of the five
affected animals. We have designated this disease
Alaskan Husky encephalopathy.
Materials and methods
Clinical evaluation and necropsy of five dogs (dogs 1–5) were performed at the College of Veterinary Medicine at Cornell University. Specimens of brain, spinal cord, peripheral nerves and visceral organs were fixed in 10% neutral buffered formalin, processed routinely in an automatic tissue processor, embedded in
paraffin, sectioned at 5 µm, and stained with hematoxylin and
eosin (H&E). Selected CNS sections were stained with Luxol-fast
blue-cresyl Echt violet and Bielschowsky’s silver stain.
Immunohistochemical examination was performed on deparaffinized sections processed by streptavidin-biotin-peroxidase complex procedure with diaminobenzidine as the chromogen. The primary antibodies against glial fibrillary acidic protein (GFAP;
Dako, polyclonal, 1 : 300) and vimentin (Dako, monoclonal, 1 : 40)
were used. Before staining for vimentin, slides were microwave
treated.
Results
Clinical findings
A detailed description of the neurological findings is reported separately [48]. In brief, the onset of clinical signs
was before 1 year of age (7–11 months) in four of the five
cases and at 2.5 years of age in other dog. The onset was
usually sudden with either ataxia (n =3) or seizures (n =
2). In two dogs, both seizures and ataxia developed during
the course of the disease. The ataxia included varying degrees of cerebellar and vestibular signs with hypermetria
and balance loss. Gait abnormalities also included hypertonicity of all four limbs and proprioceptive deficits. Most
dogs had a disturbance of their behavior varying from obtundation to propulsive pacing and apparent visual deficits.
Prehension of food was often abnormal. Decreased nociception, especially facial hypalgesia, was noted in some
animals. In most dogs the neuroanatomic diagnosis was
diffuse involvement of the brain including cerebrum,
brain stem and cerebellum. In dogs that were observed for
Fig. 1 A Bilateral and symmetrical oblique cavitation of the thalamus. B In some dogs, the thalamic lesion extends caudally to the
reticular formation in the medulla oblongata, where it retains its
oblique orientation (arrows). Note bilateral and symmetrical degeneration in the white matter of the reticulospinal and rubrospinal
tracts (asterisks). Both lesions are seen at this magnification as reduced myelin staining (LFB Luxol-fast blue). A, B Dog 1. LFB
staining; A × 3, B × 4.6
longer periods, the signs either remained static or improved,
but recurrences were common and included both gait abnormalities and seizures. One female dog (not included in
this report) died naturally at 4 years of age following a
disease course lasting over 1 year. All other animals were
euthanized between 2 and 7 months following onset of
clinical signs.
52
Pathology
Gross examination
The outer surface of the brain and spinal cord was normal.
Transverse sections of the brain revealed bilateral and
symmetrical soft gray cavities in the thalamus, which extended to the medulla in severely affected dogs (Fig. 1). In
less profoundly affected dogs, the bilateral and symmetrical cavities were segmental rather than contiguous
throughout the brain stem. The thalamus was invariably
the most extensively affected region. Thalamic cavitary
changes were oriented along an oblique dorsolateral to
ventromedial axis, resulting in a V-shaped appearance,
and involved approximately a third of the parenchyma,
measuring on average 1.5 × 0.5 cm. More caudally, the
malacic foci were markedly smaller but tended to retain
an oblique orientation. In the cerebrum, the cortical ribbon at the base of numerous sulci was attenuated and
slightly brown tinged. Such cerebral foci were randomly
distributed, although concentrated in the parietal and temporal lobes. No gross abnormalities were detected in the
spinal cord or outside the CNS.
Light microscopy
Distribution and classification of the lesions. All five
dogs had histopathological CNS lesions of similar nature
and distribution but of variable severity. Brain lesions
were found in the cerebrum, brain stem and cerebellum,
and occurred in two distribution patterns: (1) bilateral and
symmetrical degeneration within the basal nuclei, thalamus, midbrain, pons and medulla oblongata and (2) multifocally at the base of sulci in the cerebral cortex and in
the cortex of the ventral vermis of the cerebellum. In regions where gray and white matter are separated, neuroparenchymal changes primarily affected the gray matter.
In the brain stem, this predilection was less discernable.
Lesions in the spinal cord were mild, inconsistent and
limited to the white matter. All brain lesions exhibited
neuronal depletion with variable neuronal sparing, vascular prominence, spongiosis and gliosis. Distinction between
active degeneration and quiescent lesions was made. The
following were considered indicative of ongoing degeneration: marked vascular prominence, the presence of intact
and ischemic neurons, glial necrosis, mild to moderate
gliosis and an occasional mixed infiltrate of inflammatory
cells, thought to be secondary to tissue necrosis. Quiescent foci were characterized by less prominent vasculature with more advanced gliosis and neuronal loss in the
absence of ischemic neurons. Spongiosis and cavitary
changes were observed in both types of lesions. In active
degeneration, such cavities occurred in a mildly to moderately gliotic neuropil and contained gitter cells with occasional lymphocytes. In quiescent ‘burnt out’ lesions, cavities were surrounded by a sclerotic neuropil and gitter
cells were absent. Both active and inactive lesions coexisted in the same animals, and were sometimes juxtaposed
Fig. 2 A–C An inactive lesion with well-demarcated boundaries
(arrows) visible at this magnification because of associated myelin
loss. The affected area is profoundly gliotic and the center has undergone cavitation. B Neuronal survival in a gliotic region. Two
reactive gemistocytic astrocytes are indicated by arrows. C Survival of neurons with normal morphology (arrows) in a cavitated
area. A, B Dog 2, C dog 1. A LFB, × 15; B H&E, × 152; C H&E,
× 142
53
Fig. 3 A–D Thalamus. A A discrete focus with both active and
quiescent phases of degeneration. In this GFAP preparation, extensive astrogliosis is seen as punctate dark structures scattered
throughout much of the lesion. Two cavitated areas are present.
Peripheral to the gliotic region are segments undergoing active degeneration (solid arrow and open arrow), one of which (open arrow) is identified at this magnification by its lack of GFAP staining. B Higher magnification of a region undergoing active degeneration (indicated by an open arrow in A). The neuropil is edematous, partly dissolved and contains an admixture of proliferated
glial and mononuclear cells. There is conspicuous neuronal and
axonal preservation. C Focus of active degeneration (indicated by
a solid arrow in A) with vascular hypertrophy and hyperplasia,
mixed mononuclear and granulocytic infiltration, gliosis and rarefaction. D Higher magnification from the central inactive component of the lesion in A showing surviving neurons within a gliotic
neuropil (GFAP glial fibrillary acidic protein). A–D Dog 4.
A GFAP, × 175; B Bielschowsky, × 175; C H&E, × 175; D GFAP
× 350
and many foci displayed features intermediate between
these two extremes.
Thalamus. In all animals, the most extensive gross lesion
was a bilateral and symmetrical obliquely oriented cavitation situated approximately in the mid thalamus. Histologically, this corresponded to a well-demarcated focus of
severe gray matter liquefaction with lesser degeneration
in the surrounding white matter (Fig. 2). In the center of
the lesion, the neuroparenchyma had undergone almost
complete dissolution leaving an empty space traversed by
infrequent blood vessels, astrocytic processes and low
numbers of axons. At the margins of the cavities, the neuropil was replaced by an admixture of reactive gemistocytic astrocytes, gitter cells, proliferated capillaries and
surviving axons, some with focal swellings (spheroids). In
this region, and less commonly in the more frankly cavitated center, there were variable numbers of surviving
neurons, either isolated or in small groups within irregular
islands of neuropil. Most surviving neurons appeared normal but occasional swollen and chromatolytic forms were
also encountered. Despite a normal appearance in H&Estained sections, the perikaryon of some neurons in affected foci stained black with a silver stain. Typically, this
was observed in areas with features of long-standing degeneration containing low numbers of surviving neurons.
In contrast, neurons in areas of active degeneration were
not argyrophilic.
Microgliosis and astrogliosis of variable intensity were
observed in non-cavitated lesions. A GFAP preparation
emphasized the focal nature of the gliosis and the sharp
delineation between affected and unaffected parenchyma,
in which only scattered Wallerian degeneration was seen.
54
trophy and hyperplasia of endothelial cells and other
cellular elements within vascular walls as well as due to
liquefaction of the neuropil with exposure of the vasculature.
A striking component of the thalamic lesion was the
occurrence of numerous vacuolated gemistocytic astrocytes interspersed among conventional reactive astrocytes
(Fig. 4). Vacuolated gemistocytic astrocytes contained single to numerous (average 5–6/cell but at times >20) apparently empty cytoplasmic vacuoles varying in size from
<1–8 µm with an average of 4 µm The astrocytic cytoplasmic vacuolation was evident in H&E-stained slides
but was seen to advantage in GFAP preparations. Vimentin stained small numbers of these cells. Although
gemistocytic astrocytes were a common element of lesions at other sites, cytoplasmic vacuoles were not detected in astrocytes outside of the thalamus.
Non-thalamic bilateral and symmetrical lesions. Destructive bilateral and symmetrical lesions of variable severity
but less extensive in comparison to the thalamus, were
present in the dorsolateral caudate nucleus, dorsal putamen, dorsal claustrum, caudal colliculi, midbrain tegmentum and the reticular formation in the medulla oblongata.
All the lesions were morphologically similar to the thalamic degeneration, except that vacuolated astrocytes were
not detected. Silver stains showed remarkable axonal
preservation within most affected regions. Mild bilateral
and symmetrical as well as randomly scattered Wallerian
degeneration in the reticular formation, tegmentum and
the reticulo-rubrospinal upper motor neuron (UMN) tracts
was observed.
Fig. 4 A, B Thalamus. A GFAP stain of a gliotic focus demonstrates many reactive astrocytes with cytoplasmic vacuolation. A
few are indicated by arrows. B Cytoplasmic vacuoles within reactive astrocytes have sharp margins and are variably sized /thick arrows). Some vacuoles are minute, as may be barely seen in the cytoplasm of the astrocyte at the bottom right corner (thin arrow). A
Dog 1, B dog 3. A GFAP, × 186, B GFAP, × 350
In some animals, older sclerotic lesions coexisted with regions of active degeneration (Fig. 3). In these cases, a cavitated core with a gliotic rim containing surviving neurons
was in turn surrounded by zones of active degeneration.
Vessels in areas undergoing active degeneration were
more conspicuous than those in adjacent sclerotic and quiescent sites. This vascular prominence was due to hyper-
Cerebrum (Fig. 5). Within the cerebral cortex there were
multiple, apparently random foci of minimal to profound
cortical attenuation associated with laminar necrosis, neuronal depletion, neuropil loss, gliosis, spongiosis and
sometimes cavitation. As these neocortical lesions occurred most commonly at the base of sulci, they assumed
an arcuate form with the most severely affected portion at
the base of the sulcus and variable extension into the adjacent gray matter of the cortex.
Although degenerative changes occurred in a laminar
fashion, the neuronal layers affected were inconsistent. In
some foci, the superficial and middle cerebral laminae
were involved with relative sparing of deeper laminae,
while in others the converse was observed.
Neuronal depletion varied from mild to profound. In
general, neuronal loss was seen as zones of gliotic neuropil containing a diminished complement of neurons and
such changes were a regular finding in all animals. In active lesions, the surrounding neuropil was sometimes only
minimally gliotic, imparting the impression of neuronal
‘drop out’. In more advanced lesions the neuropil was collapsed, the gliosis more extensive and the neuronal loss
more dramatic. Surviving neurons, both large and small
and mostly morphologically normal, were often maloriented and haphazardly scattered within the attenuated
neuropil, presumably due to parenchymal collapse.
55
Fig. 5 A–F Cerebrum. A An active lesion at the base of a sulcus.
The lesion has an arcuate outline, identified at this magnification by
vascular prominence in the affected segment. The vascular prominence is due to hypertrophy and hyperplasia of vascular cells as well
as mixed perivascular inflammatory infiltration. A more extensive
infiltrate of similar composition is present in the overlying
meninges. B Higher magnification of an area included in A. The
meningeal (arrow) and perivascular infiltrate is composed of
mononuclear cells and granulocytes, barely discernable at this magnification by their irregular nuclear contours. There is spongiosis of
the neuropil with mild to moderate gliosis. C An active lesion with
prominent vascular hyperplasia and hypertrophy in the superficial
gray matter. There is mild spongiosis, gliosis and neuronal numbers
are decreased. A thick arrow indicates mild gliosis of the glia limitans at the base of the sulcus. Relatively normal gray matter is on the
far right. D An early, active lesion with a row of necrotic ‘ischemic’
neurons (arrows). A few adjacent neurons are morphologically normal (asterisks). E An inactive lesion at the base of a sulcus (thick arrow points to vessels within the overlying meninges). The neuropil is
shrunken with pronounced gliosis and neuronal loss. Note surviving
neurons (some marked with thin arrows), unobtrusive vessels and
spongiosis in a vaguely laminar pattern. F An inactive lesion with
cavitation of the superficial gray matter extending to the overlying
meninges. The cavitated area is traversed by gliovascular trabeculae.
An asterisk indicates the base of the sulcus. A–D Dog 4, E dog 3,
F dog 1. A–F H&E; A, F × 35; B × 175; C, E × 87.5; D × 350
56
Fig. 6 A–D Cerebellum. A Well-demarcated segmental atrophy affecting contiguous folia in the vermis (asterisks). The cortex in the
most dorsal folium (top) is normal. Note also relative sparing of
more lateral gray matter (arrows). B Higher magnification of an area
in the most ventral folium in A demonstrating sparing of Purkinje
neurons (arrows with p) within a moderately gliotic neuropil. There
is subtotal atrophy of the granular cell layer with residual granule
cells visible as dark dots. Thick arrows indicate the gray and white
matter junction. A few hypertrophied astrocytes (arrows with a) are
present in the atrophic gray matter and in the underlying white mat-
ter. C A quiescent lesion with profound atrophy of all cortical layers.
Advanced fibrillary gliosis affects the molecular layer (M) and the
depleted and attenuated granular layer (G) which are separated by a
band of Bergmann’s gliosis (B). Thick arrows indicate the gray and
white matter junction. D A focus of subacute degeneration with numerous necrotic granule cell neurons seen as dark dots scattered
throughout a gliotic and edematous granular layer. There is loss of
all Purkinje neurons and Bergmann’s gliosis (B). Note a surviving
Golgi neuron (arrow with g) (M molecular layer). A, B Dog 2; C,
D dog 4. A, B LFB; C, D H&E; A × 87.5, B–D × 175
57
Spongiosis accompanied the changes described above
and similarly followed a laminar pattern. It was composed
of innumerable, mostly small vacuoles of indeterminate
location within the neuropil as well as of enlarged empty
spaces surrounding ischemic neurons, presumably representing swollen astrocytic foot processes. At some sites,
spongiosis progressed to cavitation leaving optically
empty spaces traversed by gliovascular trabeculae, at
times surrounded by histiocytes, gitter cells, lymphocytes
and eosinophils. Microgliosis and astrogliosis of variable
intensity were observed in affected neocortex. A striking
and selective decrease in GFAP-positive astrocytes within
the affected laminae of active lesions resulted in a laminar
pattern of immunoreactivity with increased numbers of
GFAP-positive reactive astrocytes above and below but
not within degenerate laminae. In contrast, quiescent lesions contained GFAP-positive astrocytes throughout the
entire width of the gray matter as well as in the underlying white matter. Similar observations were made in
GFAP preparations of brain stem lesions.
There was moderate gliosis in the white matter subjacent to affected gray matter, particularly at sites where the
cortical lesion was severe. In the white matter further
from such sites, there was often an impression of a more
widespread, milder gliotic process. Astrocytes were reactive with slightly enlarged nuclei and minimal expanded
cytoplasm. They stained positively with GFAP and vimentin, the presence of the latter intermediate filament
confirming their altered, reactive state [37]. Sporadic
spheroids and modest Wallerian degeneration, most notable in the white matter close to affected gray matter,
were also seen.
gliosis of the molecular layer. Of note was the presence of
surviving Golgi neurons of normal morphology in the gliotic granule cell layer and less commonly of a few Purkinje neurons. In some of the animals, cerebellar cortical
degeneration was associated with mild to moderate gliosis
of the fastigial and interposital cerebellar nuclei.
Cerebellar white matter changes resembled white matter changes elsewhere in the neuroaxis.
Cerebellum (Fig. 6). The cerebellar cortical lesion principally involved the ventral portion of the vermis. As in the
neocortex and brain stem, active and quiescent phases of
the lesion were identifiable, often juxtaposed and clearly
demarcated from unaffected tissue. In active lesions, there
was partial depletion of granular neurons, the granule cell
layer was spongiotic, expanded by edema and contained
large amounts of pyknotic and karyorrhectic nuclear debris. These changes were accompanied by loss of Purkinje
neurons, astrocytic (Bergmann’s) gliosis, mild to moderate
granular layer gliosis and mild hypertrophy of capillary
endothelial cells. Active lesions progressed through intermediate stages characterized generally by an increasing
degree of neuronal depletion and gliosis with decreasing
amount of nuclear debris, edema and spongiosis. Segmentally in affected areas, Purkinje neurons of normal morphology were seen immediately adjacent to numerous pyknotic granular neurons, possibly implying that in some
locations, loss of granular neurons preceded depletion of
Purkinje neurons.
In the fully developed ‘end stage’ lesion, which predominated, cerebellar folia were markedly attenuated with
all cortical layers atrophic and collapsed. There was widespread loss of Purkinje neurons, advanced Bergmann’s
gliosis, complete depletion of the granule cell layer, severe gliosis of the depleted granule cell layer and milder
We describe a novel incapacitating and ultimately fatal familial neurodegenerative disorder affecting Alaskan
husky dogs. Onset of neurological deficits was acute and
occurred in most cases (four of the five animals) before 1
year of age. Neurological signs included ataxia, seizures,
behavioral abnormalities, apparent blindness, facial hypalgesia, loss of conscious proprioception, and difficulties
in the prehension of food. The neurological disorder was
episodic. In dogs allowed to survive, gradual improvement after the acute deterioration of neurological function
was observed. However, recurrences were common and
led to euthanasia in most cases.
In addition to the five Alaskan Husky dogs included in
this study, one of us (A.D.) received in consultation
histopathological slides of autopsy material from six other
Alaskan Husky dogs with similar lesions. To date, we
have examined autopsy material from a total of 11 spontaneous cases (5 males and 6 females) of this disorder in
seven litters of Alaskan Husky dogs from five kennels in
the USA. The incidence of the disease is probably higher,
as on several occasions littermates of affected dogs were
euthanized following the onset of characteristic neurological deficits but pathological studies were not pursued.
Spinal cord. Two dogs had spinal cord lesions of significant severity. In these animals, there was a discrete bilateral and symmetrical C-shaped band of ongoing Wallerian
degeneration and moderate astrogliosis situated in the
dorsal half of the lateral funiculus. This well-demarcated,
approximately 1-mm-wide band situated deep in the dorsolateral funiculus was evident throughout the entire
length of the spinal cord, but was most severe in the cervical portion. Anatomically, this distribution corresponds
to descending UMN axons running within the reticulorubrospinal tract. A second bilateral and symmetrical focus of moderate Wallerian degeneration accompanied by
mild gliosis was present in the ventral funiculus flanking
the ventral sulcus. Also here, the cervical spinal cord
showed the greatest degree of involvement. In other dogs,
spinal cord lesions were inconspicuous and consisted of
minimal to mild active Wallerian degeneration, most often
involving the lateral funiculus in the cervical spinal cord.
None of the dogs had lesions in the gray matter of the
spinal cord.
Discussion
58
Neuroanatomical correlation
Some of the clinical signs in these dogs can be correlated
with the location of structural lesions observed on gross
and microscopic examination of the CNS. Neurological
signs may also reflect a functional disturbance of neuronal
populations not revealed by light microscopy. This is
common in metabolic disorders. The neocortical or thalamic lesion could be the site of seizure initiation. Damage
to thalamic relay nuclei may account for nasal hypalgesia
and loss of conscious proprioception. Lesions in the reticular formation could explain some of the other neurological deficits. Dysfunction of the pontine and medullary
component of the reticular formation may be responsible
for the UMN deficits in the gait. Involvement of the ascending component, specifically the ascending reticular
activating system, could contribute to the suppressed sensorium. Thalamic and reticular formation lesions may
have led to the frequently observed difficulties in prehension of food. The propulsive tendencies are difficult to localize but often involve the motor basal nuclei, some of
which are affected in dogs with this encephalopathy (caudate nucleus, putamen and claustrum). The structural basis for the visual deficits is unknown. The clinical signs
support a central visual problem, but the cerebral lesion is
unlikely to be related to these deficits, as it is segmental
and more prevalent in the parietal and temporal lobes
rather than the occipital lobe. No consistent lesions were
present in the retina, optic nerve, optic chiasm, optic tract
or lateral geniculate nucleus in the thalamus. The cerebellar vestibular component of the gait disorder implies the
presence of further neuronal dysfunction than is evident in
the limited cortical degeneration of the ventral vermis.
Neuropathology
Thalamus and other bilateral and symmetrical lesions
In general, bilateral and symmetrical CNS lesions are
thought to be due to either metabolic aberrations (neurodegenerative disorders and toxicoses) or are determined
by vascular anatomy, regardless of whether they involve
the white matter, gray matter or both. Consistent neuronal
and axonal survival, a prominent feature of this canine encephalopathy, renders ischemia unlikely. Ischemia is expected to cause non-selective destruction, or if less severe,
to primarily involve neurons [24]. Intoxication by an exogenous agent is unlikely, given the widely scattered origin of the animals. We propose a metabolic derangement,
presumably hereditary in this breed, as the cause of this
neurodegeneration. Initial pedigree studies and test mating suggest an inherited basis with an autosomal recessive
mode of inheritance (J.J.W., unpublished).
In man, bilateral and symmetrical brain stem lesions
with tissue destruction, vascular proliferation and variable
neuronal survival may be seen either in LS or Wernicke’s
encephalopathy. These conditions can be differentiated
according to neuropathological [27] and clinical [35] crite-
ria. Similar neuropathological findings are described in
several spontaneous (see below) and experimental [36]
disorders of animals. In dogs, thiamine deficiency causes
well-demarcated bilateral and symmetrical spongy change
and necrosis of many brain stem nuclei. The caudal colliculus is the most severely affected structure and thalamic cavitation is lacking. Microscopically, lesions exhibit
hypertrophy and hyperplasia of endothelial and adventitial cells, gliosis, frequent hemorrhages and variable neuronal preservation [34]. The encephalopathy induced by
thiamine deficiency shares many similarities with the
Alaskan Husky encephalopathy but differs in several aspects. In Alaskan Husky encephalopathy, involvement of
the caudal colliculus is infrequent and mild, cerebral and
cerebellar cortical lesions are characteristic and hemorrhage is not a feature. Canine disorders of unknown etiology but possibly inherited, which are characterized by
symmetrical gray matter rarefaction with neuronal preservation, include a neurodegenerative condition in Australian Cattle Dogs [6] and familial cerebellar ataxia with
hydrocephalus in Bull Mastiffs [8]. The polioencephalomyelopathy of the Australian Cattle Dog differs from the
Alaskan Husky encephalopathy in its extensive spinal
cord lesions, more discrete targeting of gray matter nuclei
in the brain stem and more remarkable neuronal preservation. The lesions in the Bull Mastiffs are spongiotic rather
than frankly cavitary, their distribution is different and
they are accompanied by hydrocephalus. Lesions with
similar histopathological findings are also recognized in
farm animals. In pigs, focal symmetrical poliomalacia due
to selenium poisoning [41] or of unknown cause [52] is
well documented. Identical lesions can be produced in
pigs by the experimental administration of 6-aminonicotinamide (6-AN) [30, 53], an antimetabolite of niacin with
a selective gliotoxic effect [26]. Several outbreaks of a
neurological disorder of unknown etiology with lesions of
similar morphology in the spinal cord, brain stem and
cerebellum are documented in sheep in Africa [2] and in
cattle (multifocal subacute necrotizing encephalomyelopathy in Simmental calves [40] and focal symmetrical poliomalacia of the spinal cord in Ayrshire calves [31]).
A striking element of the thalamic lesion in Alaskan
Husky encephalopathy is the presence of vacuolated reactive gemistocytic astrocytes. Astrocytes with cytoplasmic
vacuolation are an unusual finding both in veterinary and
human neuropathology. In the polioencephalomyelopathy
of the Australian Cattle Dogs, vacuolated gemistocytic astrocytes were observed [6]. More recently, vacuolated astrocytes and perineuronal satellite cells in ganglia were observed in dogs following prolonged, low-level experimental administration of 6-AN [22]. Rarely, vacuolated astrocytes may be seen admixed among conventional reactive
astrocytes in areas of advanced gliosis in the dog (O.B.
personal observation).
Ultrastructural studies are required to identify the morphological basis of the astrocytic cytoplasmic vacuolation
in Alaskan Husky encephalopathy. In MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), smooth muscle cells and to a lesser degree endo-
59
thelial cells of blood vessels in the brain contain small
vacuoles which have been shown by ultrastructural examination to correspond to proliferated and swollen mitochondria [10, 39]. Why vacuolated reactive astrocytes are
observed only in the thalamus and not in other bilateral
and symmetrical lesions in Alaskan Husky encephalopathy is unknown. It may relate to the fact that degenerative
changes are most severe at this location.
Cerebrum
Cerebrocortical lesions in this encephalopathy bear some
resemblance to cerebrocortical necrosis (CCN)/polioencephalomalacia as encountered in the dog, but differ in
their distribution within the cortical mantle. CCN in dogs
is seen sporadically, either alone or in conjunction with lesions elsewhere in the brain. In some cases, the underlying cause is known, e.g., intraoperative cardiac arrest
[32], cyanide poisoning [18], thiamine deficiency [34],
lead poisoning [54] or hypoglycemia [23]. Sometimes
the cause is undetermined [3, 18]. In other cases, CCN occurs with coexistent conditions such as meningitis, thromboembolic disease, atherosclerosis [3], canine distemper
encephalitis, infectious canine hepatitis [18], or gastroenteritis [13], but the relationship between the two is unclear. Whereas cerebrocortical lesions in Alaskan Husky
encephalopathy occur exclusively at the base of sulci, a
similar predilection has not been noted in canine CCN. In
man, the tendency of a circulatory disturbance to involve
gray matter at the base of sulci rather than at their crest is
well recognized [7, 19]. In contrast, this predilection has
not been well documented in veterinary neuropathology.
Occasionally in the Alaskan Husky encephalopathy, an
inflammatory infiltrate comprising histiocytes as well as
neutrophils and eosinophils is observed in acutely compromised regions and is interpreted as secondary to tissue
necrosis. The occasional eosinophilic component is unusual but is well documented in cerebrocortical necrosis
(‘salt poisoning’) and in focal symmetrical poliomyelomalacia [52] in pigs. It could be suggested that the cortical lesion is secondary to seizure activity. Although
seizures are common in Alaskan Husky encephalopathy,
they were not present in three of the five dogs in this report. Further, the association between seizure disorders
and brain injury in domestic animals is much less clearly
established than in human subjects. In dogs with idiopathic epilepsy, ischemic neuronal change rarely occurs
[42]. Cortical necrosis, interpreted as seizure induced, is
seen in some cases of canine distemper encephalitis. The
pyriform lobe and the hippocampus are selectively affected [3].
Cerebellum
The cerebellar cortical lesion, which mainly involves the
ventral vermis, shares many similarities with degenerative
changes seen in other areas, but progression to cavitation
does not occur. Quiescent ‘burnt out’ lesions involving all
cortical layers are the most frequent finding and resemble
long-standing lesions of cerebellar cortical abiotrophy, as
seen in dogs, However, survival of isolated Golgi neurons
and rarely Purkinje neurons would be unusual in a cerebellar abiotrophy or a hypoxic lesion, to which Purkinje
neurons are particularly susceptible [16]. Gliosis of the
fastigial and interposital cerebellar nuclei is probably a reflection of trans-synaptic degeneration following loss of
Purkinje neurons in the vermis. In animals, selective involvement of the ventral vermis was reported in five of
six dogs with thiamine deficiency [34] and in three of five
animals with cardiac arrest [32].
White matter
Degenerative changes in this encephalopathy preferentially affect the gray matter but the white matter is not entirely spared. In brain stem lesions for example, the destructive process frequently involves surrounding white
matter. In the cerebrum, cerebellum and spinal cord, white
matter lesions are either necrotizing, undergoing Wallerian degeneration, pure gliosis, or a mixture. While degenerative white matter changes are clearly accentuated in
the vicinity of gray matter lesions, they are not limited
to these regions. Some of the Wallerian degeneration in
the midbrain, medulla and spinal cord is bilateral and
symmetrical and anatomically consistent with UMN degeneration of the reticulo- and rubrospinal tracts, possibly
reflecting the bilateral and symmetrical lesion in the reticular formation. Widespread gliosis may reflect cerebral
edema which is prone to occur in white matter. Such pure
gliosis, perhaps the most pervasive white matter lesion in
this condition, is widespread and often mild and thus difficult to delineate.
Nature and distribution of the lesions
Irrespective of site in the neuroaxis, affected regions share
several histopathological similarities. They primarily involve the gray matter, tissue destruction and neuronal loss
is seen concomitant with variable neuronal sparing, there
is striking hypertrophy and hyperplasia of capillaries,
spongiosis and gliosis are prominent, and active and inactive phases of the degenerative process are discernable.
White matter changes seem to be largely reactive. The
classification of lesions into active, quiescent and intermediate stages based on morphological features, is based
on the definitions of Cavanagh and Harding [9] who
analysed a series of cases with LS. It seems possible that
areas of tissue destruction with partial neuronal sparing,
as seen in this canine encephalopathy, could be the result
of a primary gliopathic process with neuronal loss a secondary event. Studies with glial toxins such as 6-AN,
which produce lesions of similar morphology, are supportive of this contention. It remains to be determined
whether the transient vacuolation of astrocytes in Alaskan
60
Table 2 Suspecteda spontaneous mitochondrial diseases in domestic animals (EM electron microscopy)
Species
No.
cases
Irish Terrier
1
Sussex Spaniela
1
Simmental and
Simmental cross
calves
> 30
Organ affected and main
clinical signs
Features suggesting mitochondrial involvement
Reference
Skeletal muscle; stiff gait,
difficulty in swallowing,
muscle atrophy with high tone
Skeletal muscle; exercise
intolerance
CNS; pelvic limb ataxia,
caudal paresis, sudden death
Degenerative myopathic changes by histology,
abnormal enzyme distribution by histochemistry,
metabolic defect in isolated mitochondria
Lactic acidosis, pyruvate dehydrogenase deficiency
[51]
Old English
Sheepdogs
2
Skeletal muscle; episodic
weakness
Arabian
horsea
1
Skeletal muscle; profound
exercise intolerance
Jack Russell
Terrier
1
Skeletal muscle; progressive
exercise intolerance
Swaledale
lambs
Not
given
CNS
Australian
Cattle dogs
3
CNS; seizures with progression
to spastic tetraparesis
English
Springer
Spaniel
Dogs
1
CNS; ataxia, mild behavioral
abnormalities
a Enzyme
25
Skeletal muscle; myalgia,
weakness, muscle atrophy
Bilateral and symmetrical malacic lesions in brain
stem (olivary nucleus most consistent) and in some
cases spinal cord with hypertrophied capillaries and
frequent neuronal preservation
Exertional lactic acidosis; EM: excessive numbers
of mitochondria and glycogen accumulation in
skeletal myofibers. One dog had scattered ragged
red fibers
Lactic acidosis, a few ragged red fibers; EM:
aggregates of large mitochondria with bizarre
cristae, deficiency of Complex I respiratory chain
enzyme documented
Lactic acidosis, ragged red fibers; EM: large
subsarcolemmal accumulations of normal
mitochondria
Increased CSF lactate, bilateral and symmetrical
brain stem lesions with neuronal sparing
periaqueductal gray matter, olives and thalamus
Bilateral and symmetrical cavitating lesions in the
brain stem and spinal cord with neuronal sparing;
EM: increased numbers of morphologically normal
mitochondria in astrocytes
Marked atrophy of optic nerves and tract, bilateral
and symmetrical spongiosis in the brain stem; EM:
mitochondria with abnormal morphology in neurons
Resting lactic acidosis, abnormal accumulation of
lipid primarily in type 1 fibers
[20]
[14, 17, 40]
[4]
[44]
[29]
[28]
[6]
[5]
[38]
deficiency demonstrated
Husky encephalopathy is a reflection of a gliocentric degenerative process or a nonspecific event. The topography
of Alaskan Husky encephalopathy lesions in the neuroaxis is unexplained, as is often the case with neurodegenerative diseases of animals and man. There is some
overlap in the distribution of extracortical lesions between
Alaskan Husky encephalopathy and canine CCN due to
various causes [3]. As some cases of canine CCN are
caused by energy deprivation (thiamine deficiency,
cyanide poisoning), an overlap is not surprising.
Comparison of Alaskan Husky encephalopathy and LD
Since its initial description in 1951 [25], LS/LD subacute
necrotizing encephalomyelopathy has been recognized in
man as a neuropathological syndrome [9, 27, 45, 46, 50].
In the last decade, numerous investigations have shed
light on the clinical recognition [21, 49], neuroimaging
findings [43], enzymatic deficiencies, genetic mutations
and inheritance patterns [1, 12, 15, 45] of this heterogeneous disorder. The pathological diagnosis of LS rests
upon the demonstration of characteristic lesions in the
brain stem and lateral walls of the third ventricle, primarily in its caudal part. Brain lesions are usually bilateral
and symmetrical and show a tendency to be non-contiguous. They do not respect gray and white matter boundaries, especially in the brain stem [27]. Characteristic features of acute lesions are loosening and spongiosis of the
neuropil followed by necrosis. There is capillary proliferation, macrophage infiltration, gliosis and occasional
perivascular cuffs. An important feature is the relative
preservation of neurons. Findings may vary in different
regions of the same case; while some areas are ‘end stage’
lesions, others show florid changes [16]. The destructive
process is episodic and total tissue damage is cumulative
[9]. In human autopsy material, lesions with quiescent
features predominate [9]. Astrocytic vacuolation is not described in LS.
The lesions of LS bear a considerable resemblance in
their distribution and quality to Alaskan Husky encephalopathy. There are differences in the topography of
lesions between the canine and human disorders. In LS,
the most frequent involved regions are the midbrain
tegmentum and substantia nigra [9, 27], the pontine
tegmentum [27] and the medullary tegmentum [9, 27]. In-
61
volvement of the neuroaxis outside the brain stem (e.g.,
basal nuclei, corona radiata, optic nerves, cerebellum,
spinal cord) is variable. In Alaskan Husky encephalopathy,
the thalamus is the most severely affected region but is involved only in half [27] or less [9] of LS cases. Involvement of cerebral gray matter is a consistent feature of
Alaskan Husky encephalopathy. Although recognized in
LD [47], it is very uncommon and seen in only 10% [27]
or less [9] of cases. A more detailed comparison of the
distribution of lesions in LS and Alaskan Husky encephalopathy is unwarranted at this stage, in part because
the distribution of LS is very variable [27, 33, 46]. Preliminary electron microscopic examination of brain tissue
and conventional light microscopic examination of skeletal muscle in these dogs failed to detect anything but nonspecific degenerative changes, which may not be surprising. In LS, ultrastructural mitochondrial abnormalities in
the brain have beens described in very few cases [33, 50]
and are considered to be of minor diagnostic significance
[49]. Ragged red fibers are generally absent in LS [21,
49].
Proposed similarities between Alaskan Husky encephalopathy and LS do not rest solely on pathological
findings but also on the clinical presentation. Both are
mostly diseases of juvenile, or less commonly young
adult to adult onset with episodic and cumulative deterioration. This pattern is well documented in human patients
and is suggested by the history in the canine cases.
LS may be viewed as a designation for a typical constellation of brain lesions which develop in patients with a
biochemically heterogeneous group of abnormalities [12,
50]. A diagnosis of LS does not necessarily imply a mitochondrial disorder [12]. It has been suggested that LS is the
neuropathological paradigm caused by impaired oxidative
metabolism in the developing brain, irrespective of specific biochemical defects [11, 12]. At this time, the pathogenesis of this disorder is unknown. Biochemical studies
aimed at defining the role of mitochondria in this disorder
are currently underway. In domestic animals, a number of
encephalopathies and myopathies have been suspected to
be due to primary mitochondrial dysfunction (Table 2).
With a few exceptions, none of these tentative diagnoses
is supported by demonstration of enzymatic deficiencies.
In conclusion, this is a unique encephalopathy of unknown pathogenesis and undetermined mode of inheritance which affects juvenile and less commonly adult
Alaskan Husky dogs. Onset of neurological signs is acute
and the course is static with multiple recurrences. Pathologically, the disorder is characterized by a degeneration
with distinctive bilateral and symmetrical as well as multifocal distribution in the neuroaxis and by the coexistence
of lesions of different ages. Neuronal sparing in conjunction with apparently transient astrocytic vacuolation point
to a possible pathogenetic role of glial abnormality.
Recognition of this canine disorder is important both from
a differential diagnostic point of view to veterinary clinicians and pathologists as well as because of its potential
use as an animal model, should mitochondria be demonstrated to play a primary role in the degenerative process.
Acknowledgements This study was supported by the Zipporah S.
Fleisher Fund for Canine Neurologic Research. The authors thank
Dr. Roger P. Pitts of Duluth, Minnesota for initiating this study,
Dr. Susan Morgello of the Division of Neuropathology, Department of Pathology, The Mount Sinai Medical Center for her informative discussions of comparative neuropathology, Dr. Victor L.
F. Friedrich of the Brookdale Center for Molecular and Developmental Biology, The Mount Sinai Medical Center, New York, NY
for his assistance with ultrastructural studies and Dr. T. Robinson
who wrote the first detailed description of this condition in his final year at the College of Veterinary Medicine, Cornell University.
The expert technical support of Ms. Joy Cramer, Ms. Tina Smith
and Ms. Alexis Wenski-Roberts is greatly appreciated.
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