Comprehensive diagnostics in a case of hereditary diffuse leukodystrophy with spheroids
Meyer-Ohlendorf et al. BMC Neurology
Comprehensive diagnostics in a case of hereditary diffuse leukodystrophy with spheroids
Marie Meyer-Ohlendorf 3
Anne Braczynski 2
Omar Al-Qaisi 1
Florian Gessler 6
Saskia Biskup 4 5
Lutz Weise 6
Joachim P. Steinbach 0
Marlies Wagner 1
Michel Mittelbronn 2
Oliver Bähr 0
0 Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University , Schleusenweg 2-16, 60528 Frankfurt , Germany
1 Institute of Neuroradiology, Goethe University Hospital , Frankfurt , Germany
2 Edinger Institute (Institute of Neurology), Goethe University Hospital , Frankfurt , Germany
3 Department of Neurology, Goethe University Hospital , Frankfurt , Germany
4 Hertie Institute for Clinical Brain Research , Tübingen , Germany
5 CeGaT GmbH , Tübingen , Germany
6 Department of Neurosurgery, Goethe University Hospital , Frankfurt , Germany
Background: Hereditary diffuse leukodystrophy with spheroids is a rare type of leukoencephalopathy. Mutations in the colony stimulating factor 1 receptor have recently been identified to be the cause of this microgliopathy. Clinical and radiological presentation can often misguide physicians during the diagnosis of patients with this underdiagnosed disease. Case presentation: We present a 29 year-old woman with a rapid course of hereditary diffuse leukodystrophy with spheroids. She mainly showed cognitive impairment and severe motor dysfunctions. Her MRI showed spotted and confluent hyperintensities of the white matter on T2-weighted images involving the corticospinal tract as well as the corpus callosum. Further, those lesions showed striking restricted diffusion. As this restricted diffusion in all areas showing signs of leukoencephalopathy was so impressive we searched Medline for these terms and got hereditary diffuse leukodystrophy with spheroids as one of the first results. After a comprehensive diagnostic workup and exclusion of other leukoencephalopathies, stereotactic biopsy and genetic testing confirmed the diagnosis. Conclusion: This case points out at two important features of hereditary diffuse leukodystrophy with spheroids being spotted and/or confluent leukoencephalopathy with areas of restricted diffusion. This might help to identify more patients with this underdiagnosed disease. Moreover, the rapid clinical course in our patient raises the question whether the relatively pronounced areas of restricted diffusion are indicative of a more acute progression of the disease.
HDLS; Leukoencephalopathy; MR spectroscopy; DWI; ADC; Restricted diffusion; CSF1R; Electron microscopy
Hereditary diffuse leukodystrophy with spheroids (HDLS)
is a rare autosomal dominantly inherited disease that
occurs in both familial and sporadic forms . The median
age of onset is in the fourth or fifth decade, and the
reported range is from 8 to 78 years . The disease
inevitably leads to death within a few years after onset, however
single cases with survival times of several decades have
been described . The clinical presentation can be
variable including cognitive and behavioral changes, motor
dysfunctions as well as seizures, ataxia and parkinsonism.
Therefore clinical misdiagnoses such as multiple sclerosis
(MS), frontotemporal dementia (FTD), corticobasal
syndrome (CBS) or atypical cerebral autosomal-dominant
arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) are common in HDLS patient.
Neuropathological features, which were first described in 1984
by Axelsson et al. comprise of widespread loss of myelin
and the presence of neuroaxonal spheroids . Typical
changes seen in the MRI are predominantly bifrontal
T2hyperintense white matter lesions with deep and
subcortical involvement [4, 5]. Also the corpus callosum and the
corticospinal tracts are usually involved with lack of
significant gray matter pathology . Sundal et al. recently
developed an HDLS MRI severity score showing that
HDLS first manifests focally in the white matter and
finally reaches a generalized confluent stage during disease
progression . Especially in early stages of the disease,
MRI lesions can be misinterpreted as demyelinating or
ischemic lesions or small vessel disease. Since clinical
presentation is variable and also the changes in MRI are
not specific, genetic testing or pathological examination is
needed to confirm the diagnosis of HDLS. Just recently,
mutations in the tyrosine kinase domain of the colony
stimulating factor receptor 1 (encoded by the CSF1R gene
on chromosome 5q32) have been described to be
causative for the disease . The CSF1R plays an important role
in microglial functioning. It is a cell surface receptor for
the cytokine CSF-1 that regulates mononuclear phagocytic
cells, including microglia of the central nervous system
. Microglial dysfunction is therefore believed to play a
central role in the pathogenesis of HDLS.
Here we report on a case of a 29 year-old female
suffering from hereditary diffuse leukodystrophy with spheroids,
which was confirmed by a stereotactic biopsy as well as
genetic testing. We found a mutation of the colony
stimulating factor 1 receptor (CSF1R) at c.2381 T > C (p.I794T)
that was previously described in one patient to be
causative for HDLS. Notably, a Medline search with the two
most conspicuous features of this case suggested the
diagnosis of HDLS before biopsy or genetic testing were done.
We report on a 29 year-old female patient who
presented with a slow onset of gait disturbance, spasticity,
ataxia, dysarthria and cognitive decline developing over
a peroid of just 4 months. The patient formerly had been
healthy and the family history was unremarkable with
the exception of her grandfather who had died from
Alzheimer’s disease. In the clinical examination she
showed anisocoria (L > R), a discrete left facial nerve
palsy, a spasticity with dyskinetic movements of the left
upper and lower limb, brisk tendon reflexes at both
knees and ankles with a positive Babinski sign on both
sides and an ataxic gait with small steps. Furthermore
she displayed a staccato speech with dystonic
movements of the mandibular muscles without any signs of
aphasia. She was apraxic throughout the examination
when being asked to follow basic instructions. Otherwise
the general physical and neurological examination as
well as the medical and developmental history were
unremarkable with no severe neonatal or infantile illnesses.
There was no history of medication or substance abuse.
The following investigations were all normal: Routine
blood analysis, search for infectious diseases (HIV, Borrelia
burgdorferi, Treponema pallidum, Hepatitis B/C, HSV,
VZV), thyroid function tests (TSH, fT3/4, TSH
receptor antibodies, thyroperoxidase antibodies, thyroglobulin
antibodies), metabolic investigations (α-galactosidase A,
very long chain fatty acids, arylsulfatase A, beta-
galactocerebrosidase, hexosaminidase A/B, folate, vitamine B12,
methylmalonic acid, homocystein, coeruloplasmin),
vasculitis screen (ANA, ANCA, RF, Cardiolipin) as well as the
cerebral angiography and cerebrospinal fluid analyses
(glucose, proteins, cells). The electroneuromyography and
the electroencephalogram did not reveal any specific
MRI showed well-circumscribed, spotted and confluent
hyperintensities on T2- and FLAIR-weighted images
symmetrically in the periventricular white matter and in
the corpus callosum (Fig. 1a + c). Those changes
included and extended along the corticospinal tracts and
the subcortical white matter sparing the U-fibers. On
T1-weighted images, lesions were slightly hypo- to
hyperintense, and after intravenous gadolinium application,
no contrast enhancement was seen (Fig. 1d). Lesions
showed strikingly restricted diffusion with decreased
ADC-values (Fig. 1b). DSC perfusion did not reveal any
changes of CBF or CBV (not shown). Compared with
normal appearing white matter, 1H-MR-spectroscopy
(TE 35 ms) of the affected areas revealed an unspecific
pattern with an increased choline-peak (131 %), a
decreased peak of N-acetylaspartate (31 %), and a decreased
creatine-peak (73 %), while no lactate- or lipid-peaks were
found (Fig. 2). On CT, those areas showed hypodensity,
and small calcifications were found within the lesions
symmetrically in the frontal white matter adjacent to the
callosal truncus and in the callosal splenium (Fig. 1e).
Conventional angiography of the extra- and intracranial
vessel was unremarkable and excluded signs of vasculitis
As all examinations at that point were not clearly
indicative for a specific disease we referred the patient for a
stereotactic brain biopsy.
Biopsy specimens from the stereotactic biopsy showed
CNS tissue with signs of reactive gliosis and extensive
infiltration with CD68-positive macrophages.
Furthermore, many axonal spheroids were seen which stained
positive for neurofilament (NF) and amyloid precursor
protein (APP). The Ki67 proliferation rate was not
increased. The myelin was mainly preserved (Fig. 3). In
summary, we did not observe hints for an inflammatory
or a primary demyelinating disease. JC-virus in situ
hybridization to exclude the possibility of a progressive
multifocal encephalopathy was negative. The brain biopsy
specimens were also negative for CMV, EBV, HSV1/2, as
well as VZV. CSF1R immunohistochemistry was negative
while control samples revealed positive staining results
(Fig. 4). Electron microscopy revealed regularly myelinated
axons however several axonal globular inclusions (Fig. 5).
The initial descriptive neuropathological diagnosis was
leukoencephalopathy with extensive axonal spheroids.
Following the algorithm approach to adult-onset
leukodystrophies of Alturkustani and colleagues, we finally favored
an adult-onset leukoencephalopathy/leukodystrophy with
Fig. 1 Neuroradiological findings. a MRI shows confluent hyperintense changes of the white matter on T2-weighted images, predominantly
involving the pyramidal tract. b All areas displayed restricted diffusion, last image in row shows decreased values on ADC (white arrows). c Involvement
of the corpus callosum on sagittal FLAIR (left) and coronal T2-weighted images (right). d Lack of contrast enhancement on T1-weighted images before
(left) and after application of gadolinium (right). e On computed tomography two spots of calcification are seen in both frontal lobes
axonal spheroids (ALAS) related to CSF1R mutation .
As other adult leukoencephalopathies/leukodystrophies do
usually not go along with the formation of axonal
spheroids, our main differential diagnosis was Nasu-Hakola’s
disease related to TREM2/DAP12 mutations, however
since bone cysts and lipodystrophy were not reported in
our patient, this diagnosis was rather unlikely.
The genetic testing revealed a heterozygous mutation in
exon 18 (c.2381 T > C) of the CSF1R-gene leading to a
change in the amino acid sequence (p.I794T). This
mutation has been previously described in a family with
clinically diagnosed atypical CADASIL syndrome . As
our patient’s parents were not available for testing and
Fig. 2 MR spectroscopy. a Chemical-shift-imaging shows a choline “hot spot” (yellow and red) within the lesions. b MR spectrum in the left lesion
indicates not only increased choline level, but also decreased NAA- and creatine-level, while no lactate- or lipid-peak was detectable
Fig. 3 Light microscopy. Histological (a, b) and immunohistochemical (c-h) stainings. Biopsy specimens showing many reactive astrocytes (asterisks,
a, b) on a loosened fibrillary CNS matrix. No proliferative activity is observed (c). Reactive astrocytes are strongly GFAP-positive (asterisk, d). MBP-positive
myelin sheats are largely preserved (e). Numerous CD68-positive macrophages (arrow head, f) infiltrating CNS tissue were observed. NF-positive
swollen axons (g) as well as NF- and APP-positive axonal spheroids (circle, g, h). (scale bares = 100 μm)
Fig. 4 Immunohistochemistry for CSFR1. CSFR1 immunohistochemistry of a stereotactic biopsy sample (a) and on tonsil (b), the latter serving as
positive control tissue (scale bares = 100 μm). Despite proper control, no CSFR1-signal was detected in our patient
Fig. 5 Electron microscopy. Electron microscopy showing brain tissue with regularly myelinated axons (arrow heads, a + b). Intra-axonal globular
inclusions (asterisk, b) were observed reflecting the pathological findings of axon spheroids seen in the light microscopic examination
her family history was not fully known, it is not possible
to confirm that this mutation is de novo. Nonetheless,
there was no family history of significance reported.
Here we report on a patient showing severe motor
dysfunction with gait disturbance, spasticity and ataxia.
Moreover, she suffered from progressive cognitive
impairment. One of the cerebral lesions showing a
hyperintense signal on T2 sequences and restricted diffusion
was biopsied. The histology revealed the diagnosis of
HDLS, which was confirmed by genetic testing.
The clinical presentation of this patient seems to be
rather typical for HDLS, matching with previous reports.
Our findings of white matter lesions on T2 sequences
without contrast enhancement on T1 are characteristic
features in patients with HDLS. Involvement of the
corticospinal tract and the corpus callosum, as seen in our
patient has been described . However, little is known
about other radiological features of HDLS. On a CT scan
we found two spots of calcification in both frontal lobes
(Fig. 1c). This has previously been described in one
patient only . Still, the significance of this finding is
unclear. Moreover, our patient showed areas of markedly
restricted diffusion. Symmetric supra-tentorial white
matter lesions with restricted diffusion and metabolite
abnormalities in magnetic resonance proton
spectroscopy are also seen in other cerebral pathologies
including posterior reversible encephalopathy syndrome
(PRES), toxic encephalopathies, or neuronal intranuclear
inclusion disease [9–11]. In contrast to previous reports
and without exceptions, all areas altered on T2
sequences showed restricted diffusion. Notably, the
overlapping changes on T2 and DWI showed a patchy
pattern in subcortical areas, but were clearly
circumscribed in the deeper white matter (Fig. 1a and b). Large
areas of the white matter appeared to be unaffected. Our
patient was rapidly progressing and had to be referred to a
nursery home within less than 6 months from diagnosis.
She had lost the ability to communicate and was not able
to stand or walk anymore. Maybe the rather
circumscribed MRI pattern and especially the striking diffusion
restriction is indicative for a higher acuteness and thus a
more unfavorable course of the disease. A more diffuse
and patchy pattern with less prominent lesions of
restricted diffusion seems to be more common in the cases
reported so far . In this case series also two
asymptomatic patients, 29 and 69 years of age, carrying a CSF1R
mutation were examined. Interestingly, both showed T2
alterations but lacked lesions with restricted diffusion.
Regarding MR spectroscopy we found a markedly
increased level of choline while N-acetylaspartate (NAA)
was reduced. These changes have been recently reported
in three patients with HDLS . We did not find
clearly increased levels of myo-inositol or lactate. The
increase of choline usually is interpreted as a sign of
demyelination and the NAA decrease is most likely the
result of axonal damage. Both phenomena have been
described in patients with HDLS. As this spectroscopic
pattern is found in several leukoencephalopathies MR
spectroscopy does not seem to be helpful in
distinguishing the underlying diagnosis in these patients. Notably,
we did not find demyelination in the biopsy, challenging
the increased choline level as a sign of demyelination
(Figs. 3, 4 and 5). Another possible source of elevated
choline levels in our patient might be the extensive
infiltration of macrophages . The negative
immunohistochemistry for CSF1R in our patient supports the
hypothesis that haploinsufficiency may play a role in
HDLS . Konno and colleagues also found markedly
reduced CSF1R protein in Western Blots of brain tissue
from two HDLS patients.
Aside from the impressive clinical symptoms the MRI
showed alterations of the white matter on T2 sequences
with striking areas of restricted diffusion. As this
diffusion restriction on the basis of a leukoencephalopathy
was so impressive we searched for these terms in Medline
and got HDLS as one of the first results. Nonetheless, the
stereotactic biopsy was performed and corroborated the
diagnosis. Finally, the histological diagnosis was confirmed
by the genetic testing.
In conclusion, this case points out at two important
features of HDLS being spotted and/or confluent
leukoencephalopathy with areas of restricted diffusion. This
might help to identify more patients with this
underdiagnosed disease. Moreover, the clinical course in our
patient from symptom onset and diagnosis was
unfavorable and raises the question whether the pronounced
areas of restricted diffusion are indicative of a more
acute progression of the disease.
Written informed consent was obtained from the patient
for publication of this Case report and any
accompanying images. A copy of the written consent is available for
review by the Editor of this journal.
ADC: Apparent diffusion coefficient; ANA: Anti-nuclear antibodies;
ANCA: Anti-neutrophil cytoplasmic antibodies; APP: Amyloid precursor protein;
CADASIL: Cerebral autosomal-dominant arteriopathy with subcortical infarcts
and leukoencephalopathy; CBF: Cerebral blood flow; CBV: Cerebral blood
volume; CBS: Corticobasal Syndrome; CD68: Cluster of Differentiation 68
(macrophage marker); CMV: Cytomegalovirus; CSF1R: Colony stimulating
factor 1 receptor; DSC: Dynamic-susceptibility contrast; EBV: Ebstein barr
virus; FTD: Frontotemporal dementia; GFAP: Glial fibrillary acidic protein;
HE: Hematoxylin and eosin; HIV: Human immunodeficiency virus; HSV: Herpes
simplex virus; Ki67: Kiel 67 (proliferation marker); MBP: Myelin basic protein;
MS: Multiple sclerosis; NF: Neurofilament; PET: Positron emission tomography;
PRES: Posterior reversible encephalopathy syndrome; RF: Rheumatic factor;
TSH: Thyroid stimulating hormone; VZV: Varicella zoster virus.
MMO treated the patient, drafted the manuscript, participated in the
conception and design of the study. AB performed the neuropathologic
analysis and participated in the conception and design of the study.
OA performed the neuroradiologic examinations and participated in the
conception and design of the study. FG has performed the stereotatic
bioipsy and participated in the conception and design of the study.
SB performed the genetic testing. LW performed the stereotatic bioipsy
and participated in the conception and design of the study. JPS treated
the patient, participated in the conception and design of the study.
MW performed the neuroradiologic examinations and participated in the
conception and design of the study. MM performed the neuropathologic
analysis and participated in the conception and design of the study.
OB treated the patient, drafted the manuscript, participated in the
conception and design of the study. All authors read and approved
the final manuscript.
1. Rademakers R , Baker M , Nicholson AM , Rutherford NJ , Finch N , Soto-Ortolaza A , et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids . Nat Genet . 2012 ; 44 ( 2 ): 200 - 5 .
2. Mateen FJ , Keegan BM , Krecke K , Parisi JE , Trenerry MR , Pittock SJ . Sporadic leucodystrophy with neuroaxonal spheroids: persistence of DWI changes and neurocognitive profiles: a case study . J Neurol Neurosurg Psychiatry . 2010 ; 81 ( 6 ): 619 - 22 .
3. Axelsson R , Roytta M , Sourander P , Akesson HO , Andersen O. Hereditary diffuse leucoencephalopathy with spheroids . Acta Psychiatr Scand Suppl . 1984 ; 314 : 1 - 65 .
4. Karle KN , Biskup S , Schule R , Schweitzer KJ , Kruger R , Bauer P , et al. De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) . Neurology . 2013 ; 81 ( 23 ): 2039 - 44 .
5. Sundal C , Jonsson L , Ljungberg M , Zhong J , Tian W , Zhu T , et al. Different stages of white matter changes in the original HDLS family revealed by advanced MRI techniques . J Neuroimaging . 2014 ; 24 ( 5 ): 444 - 52 .
6. Sundal C , Van Gerpen JA , Nicholson AM , Wider C , Shuster EA , Aasly J , et al. MRI characteristics and scoring in HDLS due to CSF1R gene mutations . Neurology . 2012 ; 79 ( 6 ): 566 - 74 .
7. Alturkustani M , Sharma M , Hammond R , Ang LC . Adult-onset leukodystrophy: review of 3 clinicopathologic phenotypes and a proposed classification . J Neuropathol Exp Neurol . 2013 ; 72 ( 11 ): 1090 - 103 .
8. Ikeuchi T. Clinical and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) . Rinsho Shinkeigaku . 2014 ; 54 ( 12 ): 1158 - 61 .
9. Stevens CJ , Heran MK . The many faces of posterior reversible encephalopathy syndrome . Br J Radiol . 2012 ; 85 ( 1020 ): 1566 - 75 .
10. Rimkus Cde M , Andrade CS , Leite Cda C , McKinney AM , Lucato LT . Toxic leukoencephalopathies, including drug, medication, environmental, and radiation-induced encephalopathic syndromes . Semin Ultrasound CT MR . 2014 ; 35 ( 2 ): 97 - 117 .
11. Sone J , Kitagawa N , Sugawara E , Iguchi M , Nakamura R , Koike H , et al. Neuronal intranuclear inclusion disease cases with leukoencephalopathy diagnosed via skin biopsy . J Neurol Neurosurg Psychiatry . 2014 ; 85 ( 3 ): 354 - 6 .
12. Bender B , Klose U , Lindig T , Biskup S , Nagele T , Schols L , et al. Imaging features in conventional MRI, spectroscopy and diffusion weighted images of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) . J Neurol . 2014 ; 261 ( 12 ): 2351 - 9 .
13. Brenner RE , Munro PM , Williams SC , Bell JD , Barker GJ , Hawkins CP , et al. The proton NMR spectrum in acute EAE: the significance of the change in the Cho:Cr ratio . Magn Reson Med . 1993 ; 29 ( 6 ): 737 - 45 .
14. Konno T , Tada M , Koyama A , Nozaki H , Harigaya Y , Nishimiya J , et al. Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS . Neurology. 2014 ; 82 ( 2 ): 139 - 48 .