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\begin{document}

\title{Tuberculous meningitis and Nonconvulsive status epilepticus: a Case
Report}



\author[1]{SeyedehNarges  Tabatabaee}%
\author[2]{Mostafa  Almasi-Dooghaee}%
\author[3]{alireza Gandomi-Mohammadabadi}%
\affil[1]{Neurology Department, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran}%
\affil[2]{1.Neurology Department, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.}%
\affil[3]{Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\begin{abstract}
sputum acid-fast bacilli were positive and anti-TB treatment was
started. Her cerebrospinal fluid results were normal except for a
positive nested polymerase chain reaction (PCR) for tuberculous. She
responded to protocol for treatment of status epilepticus and anti-TBM
treatment and her level of consciousness improved and she became fully
aware%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Nonconvulsive status epilepticus (NCSE) is a serious epileptic condition
in which there is minimal or no motor activity. Electrical activity in
NCSE is continuous, lasting at least 30 minutes and leads to changes in
mental or behavioral status (1, 2). NCSE is relatively common and
constitutes 20--25\% of all status epilepticus cases (3). It is often
difficult to diagnose NCSE, as there is minimal or no objective
convulsive activity and many other conditions can change the mental
status in predisposing conditions of NCSE. The underdiagnosis may lead
to detrimental results (4).

Treatment can be delayed as mental status changes without obvious
convulsions. Treatment is not simple and depends on many factors,
including the etiology, electroencephalogram (EEG) findings, and the
patient's clinical condition(3). Etiologies include idiopathic epilepsy
syndrome, metabolic disorders, trauma, brain tumors, cerebral hypoxia,
and infectious diseases (5).

Tuberculous meningoencephalitis (TBM) compromise 1\% of all TB cases
(6). It is a life-threatening form of central nervous system infection,
with significantly higher mortality and neurological impairment among
infected people. TBM has a subacute onset of symptoms with non-specific
clinical signs that may persist for weeks, often making early diagnosis
difficult. It is characterized by fever, headache, vomiting, focal
neurological signs or coma (7).

Seizures have been reported in 17\% to 93\% of patients with TBM (8).
The seizures in TBM can be either focal or generalized tonic-clonic
seizure and convulsive or non-convulsive status epilepticus (9). The
etiology of TBM seizures is multifactorial and has been identified
independently or in combination due to meningeal irritation, cerebral
edema, tuberculoma, infarction, hydrocephalous and hyponatremia.
Seizures in TBM can occur during the active phase or as sequel of
meningitis. It can even be the characteristic of CNS tuberculosis
(heraldic seizure) in 10\% of all patients (10).

Here we report a rare presentation of TBM where the patient presented
with NCSE and tuberculous meningitis. This case highlights the
importance of clinicians' awareness on unusual clinical presentations of
TBM, because NCSE is hard to diagnose without having it constantly in
mind and delayed diagnosis is associated with a poor prognosis.

\textbf{Case Presentation:}

A 50-year-old Iranian woman was admitted to our hospital with an
exacerbation of abnormal uterine bleeding (AUB) for total abdominal
hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO). Her history
revealed 10Kg weight loss during previous 3months, anorexia, night
sweets, nausea, vomiting and several episodes of fever and cough,for
which she hasn't seek any treatment. She had suffered primary biliary
cirrhosis (PBC) since 1999 and had been treated with ursodeoxycholic
acid (750 mg daily) without any immunosuppressive therapy. She had no
significant history of pulmonary or genital tuberculosis. She had given
birth to a son and a daughter. During her admission for TAH-BSO surgery
she had fever. The spiral chest CT-scan showed bilateral pleural
effusions without lymph node swellings with diffuse ground-glass
opacities and small centrilobular nodules. Sputum acid-fast bacilli was
positive and anti-TB treatment with isoniazid, rifampicin, ethambutol
and pyrazinamide was started. One day after TAH-BSO surgery, she
presented with acute alteration of mental status manifested with
impairment of awareness, disorientation to time, place and person and
bizarre behavior like undressing herself and urination in the ward. Next
day she became completely unresponsive, while she was fully awake. So,
she underwent neurology and psychiatry consult in the same day as it was
thought to have a psychiatric origin, as well.

Examination at presentation revealed no meningeal irritation, absent
neck stiffness, Kernig's and Brudzinski's signs with mental alterations
in the form of unawareness and unresponsiveness. The patient was
afebrile. Fundoscopy was normal with intact cranial nerves. Deep tendon
reflexes were elicited and plantar reflexes were flexor. Neurological
tests requiring cooperation such as cerebellar tests, muscle strength
examinations, and sensorium were not performed as she ignored commands,
but she moved her limbs symmetric in the bed, without any convulsive or
mini convulsive signs.

On initial presentation, routine blood tests revealed a normal white
blood cell count of 8,700/mm\textsuperscript{3}, low erythrocyte count
of 3,630,000/mm\textsuperscript{3} and hemoglobin level of 8.3 g/dL,
high C-reactive protein level of 95 mg/L (normal: \textless{}6), glucose
level of 190 mg/dL and low sodium level of 130 mmol/L. She had negative
results for human immunodeficiency virus. Other laboratory findings had
no remarkable changes.

cerebrospinal fluid (CSF) was taken immediately after neurology consult,
which is about a weak after initiation of treatment for TB. The opening
pressure was 25cmH2O, the leukocyte count was 0/\selectlanguage{greek}μ\selectlanguage{english}L, the protein level
was 36.1 mg/dL, and the glucose level was 57 mg/dL (corresponding blood
glucose level, 130 mg/dL). Tuberculous DNA polymerase chain reaction
(PCR) of CSF showed negative results, but nested PCR assay yielded a
positive result. Adenosine deaminase level was 32.4 IU/L (normal
\textless{}10 IU/L).

The EEG showed generalized 1.5- to 2-Hz continuous sharp and slow wave
activities. (figure 1), that had improved significantly after
administration of diazepam (figure 2) and after antiepileptic treatment
significant improvement in EEG trace is seen together with normal alpha
background and correction of periodic discharge waves (figure 3).

Magnetic Resonance Imaging (MRI) of the brain revealed multiple lesions
which were iso signal in T1 and low signal at center in T2, with ring
enhancement in supra and infratentorial regions of both hemispheres, at
the subcortical, white-gray matter junction. Some of them had nodular
enhancement, with moderate vasogenic edema around lesions. All of the
findings in the context of clinical features were in favor of TB (figure
4).

The patient was diagnosed as having TBM presenting with NCSE, and
treatment was started for NCSE. The protocol for treatment of status
epilepticus comprised diazepam and levetiracetam infusion, and then
treatment with the oral antiepileptic drugs. Anti-TBM treatment
consisted of four anti-tuberculosis drugs continued. The patient's
consciousness and clinical picture improved completely after the loading
dose of levetiracetam and she became entirely aware and oriented. Her
follow-up EEG improved significantly. No reoccurrence of cognitive
decline happened.

\textbf{Discussion:}

In this study, a TBM patient with NCSE is reported. The frequency of
status epilepticus in TB patients is 7.6\%.(9) ~However, to the best of
our knowledge, only 4 cases of TBM presenting with NCSE have been
reported in the literature (11-14). Seizures are reported in 50-73\% of
children, and 10-38\% of adults in the clinical course of TBM (15-17).

Both febrile and afebrile seizures can be the presenting feature of TBM
in children. The frequency of status epilepticus in TBM patients is
7.6\%. It is reported that Convulsions are a significant predictor of
mortality (18). Our patient presented with altered level of
consciousness and unresponsiveness and persistent seizure activity on
the EEG that comprised 1 to 2-Hz continuous sharp and slow wave
activity. Inconsistent with our study, a study by Arman study et al.
(11) has reported a patient with NCSE due to tuberculosis meningitis who
had right frontal 1.5- to 2-Hz continuous focal sharp and slow waves. In
contrast in Oka study et al. (13), EEG showed left frontal 2.5- to 3-Hz
repetitive focal sharp wave activity compatible with NCSE.

Continuous epileptiform EEG activity in NCSE is expected to be higher
than 2.5 Hz, whereby when epileptiform discharges are less than 2.5Hz,
one out of three other criteria is needed to confirm the diagnosis of
NCSE including presence of mini-convulsive signs, evolution in amplitude
or frequency of discharges and responsiveness to intravenous
administration of benzodiazepines (19). Our patient had no
mini-convulsive signs but she had an obvious response to intravenous
diazepam and levetiracetam, both clinically and electrically. The
patient in Arman study et al. (11) responded to diazepam and phenytoin,
followed by midazolam infusion. In Oka study et al. (13) after
anticonvulsant treatment with levetiracetam, persistent EEG activity
ceased with the recovery of consciousness

In our study, recovery of consciousness and normalization of subsequent
EEGs with antiepileptic therapy have happened. A study by Kalita et al.
(19) on the 32 patients with highly probable tuberculous meningitis have
done. Evidence of extra-CNS tuberculosis were present in 6 patients; all
had pulmonary tuberculosis. The main abnormality in their EEG was
diffuse slowing of the background activity (69\%).

Our patient had diffused sharp and wave activity with slow background
which is compatible with status epilepticus (20). Several reports
establish that 84\% of CNS tuberculoma clearly showed low signal on T2-
weight images and 16\% had lesions with central high signal thought to
represent caseating necrosis or tuberculous abscesses (21-23).

At an early stage of tuberculoma formation, the mass is isointense on
T1- and T2-weighted images and shows some contrast enhancement, that is
secondary to occurrence of inflammatory reactions and excess of giant
cells in the mass and a poor collagen capsule, that it becomes rich in
collagen, later in the course of disease. They give low signal on
T2-weighted images because of fibrosis, scar tissue (24). Rarely,
tuberculomas show calcification on CT, but it can appear as low signal
on MRI. All tuberculomas show ring or nodular contrast enhancement.

Almost one third of tuberculomas are multiple (25). Various differential
diagnosis should be considered in a patient presented with altered level
of consciousness and multiple ring-enhancing lesions, especially
neoplasms either metastasis or primary lymphoma and other infectious
diseases like fungus or bacterial endocarditis. Moreover, Tuberculomas
have a variety of different features that can mimic other
space-occupying lesions, such as neoplasms.

Metastases, multiple gliomata or meningiomas excluded by further
evaluations. No space occupying lesion was found in the chest and
abdominopelvic CT-scan. The pathology of her surgery was in favor of
diffuse granulomatous involvement.

The normal CSF glucose and protein levels are unusual but not
incompatible with the diagnosis of TB (26). Acid-fast bacilli are seen
in only 40\% cases on initial CSF examination (27). The tuberculin test
is negative in 50\% cases at presentation (28). Similar to Arman study
et al. (11) in this study, PCR of CSF was negative, but nested PCR assay
was positive. Nested PCR is a technique that reduces nonspecific
amplification of the DNA template. It increases the sensitivity and
specificity of the reaction and is useful on suboptimal nucleic acid
samples (29).

The presence of a low signal lesion on T2-weighted images that shows
ring or nodular contrast enhancement in a patient who has tuberculosis
elsewhere in the body and from a region in which tuberculosis is endemic
should suggest CNS tuberculoma.

The patient's clinical findings, unexplained acute change of
consciousness, together with chest involvement, diffuse granulomatous
infiltration in uterus and ovaries, and multiple ring enhancement
lesions in brain MRI, led to the diagnosis of TBM. The positive response
of the patient to antituberculosis treatment also supported the
diagnosis.

\textbf{Conclusion:}

The varied manifestations of CNS tuberculosis, that used to be a common
neurological disorder in developing countries, have now become relevant
worldwide. Early diagnosis and timely treatment of the disease are
critical. TBM and NCSE constitute a diagnostic challenge and both should
be considered by clinicians among the many presentations of
tuberculosis.

\textbf{Data Availability Statement (DAS)} :

The data that support the findings of this study are available from the
corresponding author, {[}Mostafa Almasi-Dooghaee ,Neurology Department,
Firoozgar Hospital, School of Medicine, Iran University of Medical
Sciences, Tehran, Iran. Email: A\_mostafa108@yahoo.com , Tell: +98 98
915 180 1384{]}, upon reasonable request.

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Figure 1: EEG trace; transverse montage (7\selectlanguage{greek}µ\selectlanguage{english}v/mm, 30mm/s), Generalized
periodic discharges with 1-2 Hz frequency superimposed on slow
background.

Figure 2: EEG trace; transverse montage (7\selectlanguage{greek}µ\selectlanguage{english}v/mm, 30mm/s), after
administration of 10mg IV Diazepam, significant improvement with some
transient sharp waves at left hemisphere and normalization of
background.

Figure 3: EEG trace; transverse montage (7\selectlanguage{greek}µ\selectlanguage{english}v/mm, 30mm/s), after
antiepileptic treatment significant improvement in EEG trace is seen,
with normal alpha background and omission of periodic discharges. In
this trace C3 \& F4 lead artifact is seen.

Figure 4: Brain MRI revealed multiple T1-weighted hyposignal (3-a) and
T2-weighted hypo/hypersignal (3-b, 3-c) lesions with ring-like
gadolinium enhancement at cerebellum and throughout the cerebellum (
3-d, 3-e, 3-f), predominantly at gray matter-white matter junction.\selectlanguage{english}
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