Acta Neuropathol (1993) 86:542 - 545

Acta
H ffiopathologica
9 Springer-Verlag 1993

Type I familial amyloid polyneuropathy and pontine haemorrhage
J. Arpa Guti6rrez 1, C. Morales 2, M. Lara 1, C. Mufioz 1, M. Garcia-Rojo 2, A. Caminero 1, M. Guti6rrez 2
1 Department of Neurology, Hospital La Paz, Avda. Ferrol, 30, 2~ E-28029 Madrid, Spain
2 Department of Pathology, Hospital La Paz, U.A. Madrid, Spain
Received: 19 March 1993/Revised: 24 May 1993/Accepted: 3 June 1993

Abstract. A Portuguese female, aged 47 years, who had
emigrated to Spain, was admitted to the hospital in 1991
for pontine haematoma. The patient, four siblings and
her father were affected by a peripheral neuropathy,
indicating autosomal dominant inheritance. The patient
presented in the 2nd decade with sensory and motor
neuropathy beginning in the lower extremities. Alternating constipation and diarrhoea, and urinary incontinence became uncontrollable. She had to be colostomised, and, eventually, confined to a wheelchair from the
age of 43. Neurological examination showed bilateral
facial involvement, and severe signs of sensory and
motor peripheral neuropathy, and later right hemiplegia. There were abnormalities of atrial rhythm and left
bundle branch block. Computerised axial tomography
and magnetic resonance images demonstrated left-sided
pontine haemorrhage. Nerve conduction studies
revealed severe diminution of motor conduction velocity
and absence or reduction of amplitude of sensory and
motor action potentials. Inanition and a respiratory
infection led to her death. Clinical diagnosis was type I
familial amyloid polyneuropathy (FAP). Postmortem
examination demonstrated amyloid deposits in peripheral nerves, including spinal roots and cranial nerves,
leptomeninges, thyroid, breasts, heart, adrenal glands,
kidneys, intestines, pancreas, and meningeal and some
pontine vascular structures. Advanced pontine haematoma was verified. Cerebral haemorrhage usually occurs
with cerebrovascular amyloidosis, but exceptionally
with FAP. A minority of patients presenting with CNS
haemorrhage showed arteriovenous malformation or
embolism [Da Silva Horta and Dias Coelho (1960) Arch
'de Vecchi' Anal Patol Med Clin 31 = 163-172]. However, amyloid deposition in some small pontine vessels
could have played a role in the pathogenesis of haemorrhage in the present case.
Key words: Familiar amyloid polyneuropathy - Central
nervous system haemorrhage - Transthyretin
Correspondence to: J. Arpa Gutidrrez

Since Andrade [1] first decribed familiar amyloid polyneuropathy (FAP) in a portuguese family in 1952, many
other families with similar manifestations have been
reported throughout the world.Today there exist over 19
types of FAP [3, 10, 12, 14, 15, 22-24]. Most types are
due to different amino acid substitutions in prealbumin
transthyretin (TTR). More than 25 variant forms of TTR
are now associated with systemic amyloidosis [2]. The
most common TTR variant is portuguese type I FAP in
which methionine is substituted for valine in monomer
position 30. At least one allele of the TTR locus in
chromosome 18 is responsible for the synthesis of
abnormal TTR [3, 10].
Type I FAP follows an autosomal dominant trait and
is initially characterized by sensory and autonomic
neuropathy mainly in the lower legs followed by motor
neuropathy. The few previously reported necropsic cases
suggest that endoneural amyloid deposits cause peripheral nerve fibre loss due to local ischaemia [8, 13].
Nonetheless, no neuropathological lesions of the central
nervous system (CNS) have been observed in type I FAR
Only one case of type I FAP with a softened area in the
temporal cortex was associated with vascular amyloid
[211.
This clinical and post-mortem report describes a
patient with type I FAP with pontine hematoma associated with intraparenchymatous vascular deposits of
amyloid.

Case report
A 47-year-old Portuguese female emigrant was admitted to our
hospital in 1991 because of right hemiplegia. The patient, her
father and four siblingshad type I FAR At the age of 15 she showed
a progressive sensory and motor loss in her lower legs as well as
constipation alternating with diarrhoea and urinary incontinence.
A colostomy had to be performed. At the age of 43 she was
confined to a wheelchair. Neurologicalexaminationshowed bilateral facial involvement, severe signs of sensory and motor
peripheral neuropathy and right hemiplegia. Heart examination
demonstrated an atrial arrythmia and the ECG showed a left

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bundle branch block. Cerebral CTscan and MR displayed images
suggesting a left-sided pontine haemorrhage. Nerve conduction
studies revealed a severe reduction of motor conduction velocity
and either an absence or reduction in amplitude of sensory and
motor action potentials. Inanition and respiratory infection led to
her death.

Post-mortem examination
Eosinophilic congophilic deposits were found in the heart, thyroid,
breast, kidney, adrenal gland, gastrointestinal tract, pancreas, and
urinary bladder, as well as in the vessels of the lung, liver, spleen,
lymph nodes, bone marrow, uterus, ovary, fallopian tubes and
around the skin glands. Under polarized light, the deposits
changed to an apple-green color. They were resistant to pretreatment with potassium permanganate, and gave a positive reaction
with thioflavine.

Neuropathology
The brain weighed 1100 g. On the left anterolateral aspect of the
pons a tan-coloured soft area was seen, which in serial sections
corresponded to a 10 x 110 x 15 mm 3 partly discoloured cystic
lesion (Fig. 1). Histological examination disclosed prominent
amyloid deposits in loose connective tissue of the arachnoid
membrane and blood vessels of cranial and spinal leptomeninges
(Fig. 2), choroid plexus and in both interstitium and vessels of
cranial and spinal roots and dorsal ganglia. No amytoid deposits
were seen in intraparenchymatous vessels except in some isolated
medium-sized vascular structures in the vicinity of pontine haemorrhage (Fig. 3). The pontine lesion showed a central haemorrhagic necrotic area, removed by abundant vacuolised macrophages that stained positively with prussian blue. At the periphery,
there was astrocitic and vascular proliferation and axonal spheroids. Spongiosis was observed in the ipsilateral mesencephalic and
medullar pyramidal tracts and in the transverse tracts. In the spinal
cord there was spongiosis throughout the columns, chromatolysis
in the motoneurons and schwannosis along the branches of the
anterior spinal artery. Sural nerve showed prominent amyloid
deposits in the small subperineural and endoneural vessels (Fig. 4).
The number of the myelinated fibres was severely decreased. In the
psoas and cuadriceps femoris muscles studied, denervation atrophy
and irregular amyloid deposits were found.

Discussion

Fig. 1. Left-sided pontine haemorrhage Loyez stain.

Fig. 2. Spinal leptomeninges: amyloid deposits in loose connective tissue and vessels. H&E, • 20

Sensory, m o t o r a n d a u t o n o m i c p o l y n e u r o p a t h y a l o n g
with gastrointestinal disturbances and arrhythmias
make-up the core features of FAR The disease usually
h a s a n i n s i d i o u s clinical o n s e t b e t w e e n 21 a n d 31 y e a r s o f
age c h a r a c t e r i s e d b y s e n s o r y a n d a u t o n o m i c n e u r o p a t h y
f o l l o w e d b y m o t o r n e u r o p a t h y , m a i n l y in legs. T h e
clinical o n s e t o c c u r r e d e a r l i e r in o u r p a t i e n t . This was
9d i a g n o s e d o n c l i n i c o p a t h o l o g i c a I g r o u n d s o f t y p e I F A P
as p r e v i o u s l y r e p o r t e d [1, 5, % 9 , 11, 17, 18, 20, 25].
Post-mortem examination demonstrated amyloid deposits in p e r i p h e r a l n e r v e s , s p i n a l r o o t s , d o r s a l r o o t g a n g l i a
a n d s o m e c r a n i a l n e r v e s , as w e l l as in m a n y o r g a n s . S o m e
a u t h o r s h a v e p r o p o s e d i s c h a e m i a as a p o s s i b l e c a u s e o f
n e r v e fibres loss. A m y l o i d d e p o s i t s c a u s e e n d o t h e l i a l
p r o l i f e r a t i o n a n d a l t e r v a s c u l a r p e r m e a b i l i t y r e s u l t i n g in

Fig. 3. Amyloid deposition in the wall of an intraparenchymatous
vessel (pons). The deposit showed apple-green birefringence with
polarising microscopy after Congo red stain, x 165

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Fig. 4. Sural nerve: vascular subperineural and endoneural amyloid deposits. Congo red pretreated with potassium permanganate.
Polarized light, x 20
o e d e m a and ischaemia [8, 13]. Nevertheless, amyloid
deposits have not been, as yet, definitively established as
a pathogenic factor of type I FAR
Vascular amyloid after the vessels penetrate the pia
has not been reported in type I FAR For this reason, no
CNS involvement has been previously reported, with
one exception [6], in which neuropathological studies
were not p e r f o r m e d and, thus, pathogenesis was not
elucidated.
The vascular disease affecting the brain in patients
with type I FAP has been poorly described in medical
literature. Only one case has been reported with temporal cortex necrosis associated with vascular amyloidosis [21]. A minority of patients with CNS h a e m o r r h a g e
have arteriovenous malformations or embolism [4].
We believe that amyloid deposits found in the small
pontine vessels in our case could have to a certain extent
caused haemorrhage. A possible embryological abnormality of vascularisation during Streeter's third phase
[19] and Padget's stages 6 and 7 [16] development of
brain sheaths could explain the exceptional amyloid
deposits in p a r e n c h y m a vessels of the CNS outside the
pia limit in our patient with type I FAR

Acknowledgement. The authors are most appreciative of the help
of Dr. Jacky Us6n for technical assistance.

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