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\begin{document}

\title{Neuro-Behcet's presenting as Solitary Midbrain lesion with Paroxysmal
Ataxia and dysarthria (PAD) Case Report}



\author[1]{Abeer Safan}%
\author[1]{Gholam Adeli}%
\author[1]{Ahmed ElSetouhy}%
\author[2]{Lina Yagan}%
\author[1]{ Mohammed  Abunaib}%
\author[1]{AHMED EL BELTAGI}%
\affil[1]{Hamad Medical Corporation}%
\affil[2]{Weill Cornell Medical College in Qatar}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Paroxysmal dysarthria and Ataxia (PDA) is a rare neurological
manifestation of stereotyped attacks of sudden ataxic symptoms lasts for
few seconds to minutes, of variable frequency. We report a case of PDA
in a 61 years old male with an isolated homogenously enhancing solitary
midbrain lesion and positive HLA-B51.%
\end{abstract}%



\sloppy


\textbf{Neuro-Behcet's presenting as Solitary Midbrain lesion with
Paroxysmal Ataxia and dysarthria (PAD) Case Report}

\textbf{Authors:} Abeer Sabry Safan\textsuperscript{1}, Ahmed EL
Beltagi\textsuperscript{2}, Ahmed El Sotouhy\textsuperscript{2}, Lina
Yagan \textsuperscript{3} , Mohammed Abunaib\textsuperscript{1}, Gholam
Adeli\textsuperscript{1}

\textsuperscript{1} Department of Neurology, Neurosciences Institute,
Hamad Medical Corporation, Doha, Qatar.

\textsuperscript{2} Department of Neuroradiology, Neurosciences
Institute, Hamad Medical Corporation, Doha, Qatar.

\textsuperscript{3} Weill Cornell Medicine of Cornell University (WCMCQ)
, Doha, Qatar.

\textbf{Correspondence:}

Dr. Abeer Sabry Safan, Neurology Department, Neurosciences Institute,
Hamad Medical Corporation, Doha, Qatar. Email: ASafan@hamad.qa

\textbf{Abstract:}

Paroxysmal dysarthria and Ataxia (PDA) is a rare neurological
manifestation of stereotyped attacks of sudden ataxic symptoms lasts for
few seconds to minutes, of variable frequency. We report a case of PDA
in a 61 years old male with an isolated homogenously enhancing solitary
midbrain lesion and positive HLA-B51 (Allele 2).

\textbf{Keywords:~} Paroxysmal Ataxia and dysarthria, Midbrain lesion,
neuro Beh\selectlanguage{ngerman}çet's disease (NBD).

\textbf{4}

\textbf{Introduction:}

Paroxysmal dysarthria and ataxia (PDA) were first described in the 1940s
by Parker and Störring as ''period ataxia,'' characterized with brief
stereotypes episodes of slurring of speech, dysprosody, and
ataxia.\textsuperscript{2} PDA is well described in multiple sclerosis
and reported in other vascular and autoimmune diseases with midbrain
lesions near or involving the red nucleus with other neurological
manifestations. It has been reported previously in a Turkish patient
with typical radiological manifestations of neuro Behçet's disease
(NBD), with many lesions in the periventricular white matter and
brainstem. \textsuperscript{4}

Few reports described solitary midbrain lesion presenting with paroxysms
of dysarthria and ataxia, with one reporting none-ataxic spontaneous
paroxysmal dysarthria associated with oligoclonal bands in CSF and
adequate response to Carbamazepine.\textsuperscript{3,6} We herein
report the first case of paroxysmal ataxia and dysarthria, with isolated
midbrain lesion with negative oligoclonal bands, and found to be HLA B51
positive.

\textbf{Case presentation:}

A 61-year-old right-handed male, non-smoker, with no known past medical
history, presented to the emergency department with five months history
of progressive episodic unprovoked dysarthria of 10-15 seconds that
occurred up to 30-40x day with intact awareness and comprehension. No
specific aggravating factors and episodes do not exhibit diurnal
variability. No history of preceding illness, trauma, and no
constitutional symptoms were present. A review of systems revealed no
extra-neurological manifestations, no mouth, genital ulcers, or blurred
vision. No relevant family history, namely PDA, cerebellar ataxia,
stammering, or stuttering.

Initial vitals were within normal parameters, temperature of 36 °C,
respiratory rate of 19 breaths per minute, blood pressure of 120/62mmHg,
oxygen saturation of 98\%, and weight of 75 kg. His neurological
examination was significant only for right dysmetria, dysdiadokokinesia,
and inability to tandem. During the consultation, episodes were
witnessed of 10-20 seconds stereotyped ataxic dysarthria with dysprosody
and none unintelligible, pointing towards paroxysmal ataxia and
dysarthria (PAD). Neuropsychological assessment was unrevealing, with
normal Mini-Mental State Examination (MMSE) 29/30.

Initial workup; MRI head with contrast, showed 5 x 8 x 6 mm homogenously
enhancing midbrain lesion a midline lesion with suspicious thickening
and increased enhancement of left third cranial nerve, that raised the
suspicion of underlying neoplastic vs. inflammatory etiology, such as
lymphoma, glial tumors, or neuro-sarcoidosis or neuro-Bechet's disease
(Figure 1 A-D). Subsequent, full-body positron emission tomography (PET)
and skeletal survey scan only showed a midline midbrain lesion with
relative hypermetabolism otherwise unrevealing, excluding malignancy or
other inflammatory processes. PET scan. Three months follow-up MRI head
showed regression of the lesion (Figure 2 A-D), indicative of likely
inflammatory process, and less likely glioma and metastasis, considering
the interval minimal regression in size.

Lumbar puncture was performed, showed no pleocytosis, normal
cerebrospinal fluid (CSF) biochemistry, culture for bacteria, and nPCR
assays for a broad panel of viruses were negative. No malignant cells
visible on cytology, and flow cytometry was not done due to paucity of
cells, and no oligoclonal bands were detected. Blood tests were within
normal parameters, including autoimmune workup and angiotensin
converting enzyme level (ACE) 61 U/L (16-85 is normal reference range).

Despite the possible differential of glial tumor or lymphoma, a brain
biopsy was deferred and not advised by the Neurosurgery team due to high
risk. Due to anatomical location and radiological features, a possible
diagnosis of neuro-Bechet's was considered. The ophthalmology
examination was normal, with no evidence of anterior or posterior
uveitis on slit-lamp examination. Further HLA B-51 (Allele 2) analysis
was requested (usually takes 3-4 weeks).

The patient was started on pulsed steroids with one gram of intravenous
methylprednisolone for five days with a tapered dose (IVMP), which did
not note any significant improvement in the frequency of his paroxysmal
ataxia and dysarthria episodes. He was started on 200mg Carbamazepine
and discharged home with regular follow-ups in the General Neurology
clinic.

On four weeks follow-up, the patient developed fever, deranged liver
function test (LFT), and severe skin maculopapular rash on more than
one-third surface area, suggestive of Anti-convulsant Hypersensitivity
Syndrome (AHS), significant enough to discontinue Carbamazepine and was
switched to Baclofen. His PDA episodes were not adequately under
control; hence a trial of Lacosamide 50mg BID controlled his PDA
episodes.

1

On five weeks follow up, HLA B-51 results reported positive, raising the
diagnosis of PAD in neuro-Behcet's with atypical radiological and
clinical findings. Per Behcet's syndrome Japanese Ministry of health and
welfare criteria, our patient has one minor criterion due to a
symptomatic central nervous system (CNS) lesion. A three-month follow-up
MRI head showed slight interval regression in the midline midbrai1n
lesion size to 4 x 7 x 5 mm in maximum AP, with decreased perilesional
edema (Figure 2 A-B).

\textbf{Discussion:}

PDA is a rare neurological manifestation of acquired conditions or
hereditary disorders, like autosomal dominant episodic dysarthria and
truncal ataxia.\textsuperscript{5} It is a well-described phenomenon in
multiple sclerosis since 1980, yet one of the least common paroxysms
encountered in clinical practice.\textsuperscript{2} Midbrain has a
pivotal role in PDA symptomatology, as Matsui et al. observed with
lesions near or within the red nucleus of the midbrain disturbing the
crossed fibers of cerebello-thalamocortical pathways in the lower
midbrain, connecting cerebellum and cortex via the superior cerebellar
peduncle. \textsuperscript{4,5}

Pathophysiology of PDA is not fully known to date, and it has been
reported in many autoimmune diseases, namely, antiphospholipid syndrome
and Behcet's disease. \textsuperscript{5,4} Behcet's syndrome is
characterized by widespread vasculitis involving arteries and venules
without preference to a specific size. Hence its variable clinical
phenotypic presentations, and highly correlated with the geographical
distribution of HLA-B51. \textsuperscript{1,2} NBS has a distinctive
lesion pattern, described in the literature as cascade sign, due to
extension of brain lesions from thalamus / Meso-diencephalon and
telencephalon to the brainstem, differentiating it from
inflammatory-demyelinating disease such as multiple sclerosis (MS).

Naci Kocer et al. In a study of 65 patients with NBS, demonstrated
intra-axial veins and small vessels pattern on MRI head; commonly, the
meso-diencephalic junction (MDJ) in 46\% of patients, followed by
Ponto-bulbar region in (40\%), the hypothalamic-thalamic region (23\%),
basal ganglia in 2\%, followed by telencephalon, cerebellum in three,
and the cervical cord.\textsuperscript{1} Such finding; support venular
involvements and supports their hypothesis of small vessel
vasculitis.\textsuperscript{1} Xia et al. and Codeluppi et al. in a case
report and case report of two patients respectively demonstrated PDA and
solitary sclerosis of the midbrain with positive CSF oligoclonal bands,
supporting demyelinating/inflammatory etiology with an adequate response
to Carbamazepine. \textsuperscript{3,6}

PDA in neuro-Behcet's disease, theoretically speaking, is expected if
lesions involve the midbrain, as seen in one previously reported case
associated with many lesions in the periventricular white matter and
brainstem correlating with a typical neuroradiological pattern of NBD
fulfilling the NBD diagnostic criteria.\textsuperscript{6} However,
isolated midbrain lesions in neuro-Behcets manifesting with isolated
midbrain lesion have never been reported, raising possible subtypes of
NBD, for which a better understanding of the disease's pathophysiology
on a molecular level is warranted. \textsuperscript{8}

PDA pathogenesis is not fully understood to date, with other variants as
Xia et al. has presented a none-ataxic PDA variant in solitary midbrain
sclerosis. Understanding midbrain PDA triggering lesions; relative to
their burden and nature (vascular, demyelinating, vasculitic) is
paramount, which would aid in better understanding of possible
pathophysiology relevant to cerebello-thalamocortical pathways, and
hence better-targeted treatment. \textsuperscript{6}

Finally, Carbamazepine has been reported to be effective in PDA-related
MS lesions, solitary sclerosis, and APLS related lesions; by opposing
the Ephaptic transmissions between contiguous
fibers.\textsuperscript{3,5} As previously, Ostermann \& Westerberg et
al. postulated that ion channel dysfunction could alter fibers and
generate axon potentials without synapses that could alter the
excitability of neighboring neurons owing to their anatomical and
electrical proximity (Ephaptic transmission). \textsuperscript{9}
Nonetheless, Carbamazepine can affect the entire axon membrane and
successfully block the Ephaptic transmission for better PDA control, but
other anti-epileptics (phenytoin, lamotrigine, acetazolamide, and
levetiracetam) have been reported to be effective as well. In our
patient, due to idiosyncratic drug-induced reaction, Carbamazepine
cannot be assessed for its effectiveness but was well controlled on
Lacosamide to date.

\textbf{DECLARATIONS}

\textbf{ACKNOWLEDGMENT}

The authors would like to acknowledge Qatar national library (QNL) for
this publication's funding.

\textbf{Ethics and consent to participate}

This case report was approved by the Hamad Medical Corporation's Medical
Research Center (Protocol number: MRC 04-21-689 )

\textbf{CONSENT}

Written informed consent was obtained from the patient for publication
for this case report,. A copy of the written consent is available for
review by the Editor of this journal.

\textbf{DATA AVAILABILITY STATEMENT}

The datasets used and/or analyzed during the current study are available
from the corresponding author on request.

\textbf{COMPETING INTEREST}

The authors have no conflict of interest to disclose.

\textbf{FUNDING}

Qatar National Library funded the open access publication fees of this
case.

\textbf{Author contributions}

Writing the initial draft of the manuscript: AS, LY, AELB

Conceptualization and supervision: AELB, AELS, GA

Medical management of the case: AS, GA, A

Revising the manuscript critically and literature review: AS, LY, AELB,
AELS,GA,A

\textbf{Appendix 1}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Name} & \textbf{Location} & \textbf{Contribution}\tabularnewline
\midrule
\endhead
Abeer Sabry Safan & Department of Neurology, Neurosciences Institute,
Hamad Medical Corporation, Doha, Qatar & Writing the initial draft of
the manuscript, medical management of the case, revising the manuscript
critically and literature review.\tabularnewline
Ahmed EL Beltagi & Department of Neuroradiology, Neurosciences
Institute, Hamad Medical Corporation, Doha, Qatar & Conceptualization
and supervision, revising the manuscript critically and literature
review, retrieving and neuroimaging annotations.\tabularnewline
Ahmed El Sotouhy & Department of Neuroradiology, Neurosciences
Institute, Hamad Medical Corporation, Doha, Qatar & Conceptualization
and supervision, revising the manuscript critically and literature
review, retrieving and neuroimaging annotations\tabularnewline
Lina Yagan & Weill Cornell Medicine of Cornell University (WCMCQ) Doha,
Qatar & Writing the initial draft of the manuscript, revising the
manuscript critically and literature review.\tabularnewline
Mohammed Abunaib & Department of Neurology, Neurosciences Institute,
Hamad Medical Corporation, Doha, Qatar & Medical management, revising
the manuscript critically and literature review.\tabularnewline
Gholam Adeli & Department of Neurology, Neurosciences Institute, Hamad
Medical Corporation, Doha, Qatar & Conceptualization and supervision,
medical management, revising the manuscript critically and literature
review.\tabularnewline
\bottomrule
\end{longtable}

\textbf{References}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
2. & Klaas JP, Burkholder DB, Singer W, Boes CJ. Harry Lee Parker and
paroxysmal dysarthria and ataxia. Neurology.
2013;80(3):311--4.\tabularnewline
3. & Xia Y, Shoemaker T, Gorelick N, McArthur JC. Solitary sclerosis
presenting as isolated spontaneous paroxysmal dysarthria.
eNeurologicalSci. 2019;14:98--100.\tabularnewline
4. & Akman-Demir FG, Eraksoy M, G\selectlanguage{ngerman}ürvit IH, Saruhan-Direskeneli G, Aral
O. Paroxysmal dysarthria and ataxia in a patient with Behçet's disease.
J Neurol. 1995;242(5):344--7.\tabularnewline
5. & Gessani A, Cavallieri F, Budriesi C, Zucchi E, Malagoli M, Contardi
S, et al. Pearls \& Oy-sters: Paroxysmal dysarthria-ataxia syndrome:
Acoustic analysis in a case of antiphospholipid syndrome: Acoustic
analysis in a case of antiphospholipid syndrome. Neurology.
2019;92(23):e2727--31.\tabularnewline
6. & Codeluppi L, Bigliardi G, Chiari A, Meletti S. Isolated paroxysmal
dysarthria caused by a single demyelinating midbrain lesion. BMJ Case
Rep. 2013;2013(oct16 1):bcr2013200777--bcr2013200777.\tabularnewline
7. 8. & Foundation Internet Services, LLC. Behcet's syndrome Japanese
ministry of health and welfare criteria {[}Internet{]}.
Merckmanuals.com. {[}cited 2021 Jun 26{]}. Available from:
https://www.merckmanuals.com/medical-calculators/BehcetsJapan.htm Sorgun
MH, Kural MA, Y\selectlanguage{ngerman}ücesan C. Clinical characteristics and prognosis of
Neuro-Behçet's disease. Eur J Rheumatol.
2018;5(4):235--9.\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
9. & Ostermann PO, Westerberg CE. Paroxysmal attacks in multiple
sclerosis. Brain. 1975;98(2):189--202.\tabularnewline
\bottomrule
\end{longtable}

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